HU210532A9 - 19,11beta-bridged steroides, process for producing them and pharmaceutical compositions containing them - Google Patents

Abstract

New 19,11 beta -bridged steroids of the general formula I <IMAGE> (I) where R1 stands for a methyl or ethyl radical, R2 for a hydrogen or chlorine atom or a C1-C4-alkyl radical, B and G, which are the same or different, respectively for a hydrogen atom, a C1-C4-alkyl radical or, together, for a second bond between the carbon atoms 6 and 7, B and R2 together for a methylene or an ethylene group, Z for the radical of a pentagonal or hexagonal ring, which is possibly substituted and possibly unsaturated, V stands for a possibly substituted carbocyclic or heterocyclic aryl radical, the ring A for <IMAGE> a) M and N together meaning a second bond or M a hydrogen atom and N a hydroxy group, X means an oxygen atom, two hydrogen atoms or a hydroxyimino grouping N DIFFERENCE OH, R3 and D, which are the same or different, respectively a hydrogen atom, a nitrile radical or a C1-C4-alkyl radical or, together, a methylene or ethylene group, E a hydrogen atom or a C1-C4-alkyl radical, D and E together meaning a second bond between carbon atoms 1 and 2 or together a methylene group <IMAGE> b) or <IMAGE> c) with R11 in the meaning of a hydrogen atom or a C1-C8-alkyl radical, are described as well as their pharmaceutically tolerated addition salts with acids. The new compounds possess valuable pharmacological properties.

Description

The present invention relates to novel 19,1 Ιβ-bridged steroids, to the preparation of compounds, to pharmaceutical compositions containing these compounds, to the use of the compounds in the preparation of medicaments, and to novel intermediates for this purpose.

The 19,1 Ιβ-bridged steroids of the present invention and their pharmaceutically acceptable acid addition salts are represented by formula (I) wherein R ^{1 is} methyl or ethyl,

R ^{2 is} hydrogen, chloro or C 1-4 alkyl,

B and G, the same or different, are each hydrogen, C 1 -C 4 alkyl, or taken together to form a second bond between C 6 and C 7,

B and R ² together are methylene or ethylene,

Z is a group of formula (a)

R ¹ is the dotted line starting from W in the formula I, which is an optional double bond

W is CH ₂ , CH, CH ₂ CH ₂ or CHCH ₂ , R 5 / R 6 -OR 7 / -C = CU

-OR ⁷ / -CO-CH ₂ -R ⁸

-CO-CH ₂ -R ⁸ / -OR ⁷

-co-ch ₂ -r ⁸ / -ch ₃

-CO-CH ₂ -R ⁸ / -H

-OR ⁷ / - (CH ₂ ) m -CH ₂ -R ⁹

-OR ⁷ / -CH = CH (OCH ₂ ) k -CH ₂ -R ⁹

-OR ¹⁰ / -H

-OR ¹⁰ / - (CH ₂ ) k C = CU or a group of formula (b) or (c)

R ^{7 is} hydrogen or C 1 -C 4 acyl, U is hydrogen, C 1 -C 4 alkyl, C 1 -C 4 hydroxyalkyl, C 1 -C 4 alkoxyalkyl or C 1 -C 4 acyloxy in the alkyl or acyl moiety -alkyl or halogen,

R ^{8 is} hydrogen, hydroxy, C 1-4 alkyl, O-alkyl or O-acyl,

^R9 is H, OH or CN, O-C1-4 alkyl or O-C 1-4 acyl group,

R ^{10 is} hydrogen, C 1 -C 10 alkyl or C 1 -C 10 acyl, m is 0, 1, 2 or 3, k is 0, 1 or 2,

A phenyl group of formula V (d) or a five- or six-membered heteroaromatic ring containing 1-2 N, O or S atoms of formula (e) wherein R ⁴ and R ^{4 are the} same or different and are both hydrogen or cyano, OR ¹¹ , -S (O) k R ⁿ , -N (O) ⁿ R ¹² -, -OSO ₂ R ¹³ -,

-P (O) (OR ¹⁴ ) 2, -SIR ¹⁴ 3 or -Sn R ¹⁴ 3, wherein k is 0,1 or 2, n is 0 or 1,

R ^{11 is} hydrogen or C 1-8 alkyl.

R ^{12 has the} same meaning as R ¹¹ , cyano or C 110 acyl,

R ^{13 is} perfluorinated C 1 -C 4 alkyl,

R ^{14 is C} 1-4 alkyl, or

R ^{11 and} R ^{12 are} one-N (O) ⁿ R ⁿ -R ¹² - one

It encloses a nitrogen atom of a 5- or 6-membered heterocyclic group, while N, O or S may be present as another heteroatom in the ring,

Y and Y 'are the same or different, each may be a direct bond, straight or branched alkylene group containing up to 20 carbon atoms, optionally having a double or triple bond, optionally having one or more oxo groups, C 1-10 acyloxy groups, -OR ¹¹ , -S (O) k R ⁿ and / or N (O) n R ^H R ¹² substituted, optionally substituted arylene, or

R ⁴ -Y and R ⁴ '-Y' together form an optionally substituted, saturated, unsaturated or aromatic 5- or 6-membered ring containing 0-2 oxygen atoms, sulfur atoms and / or -NR ¹¹ groups, with the proviso that that k and n are only greater than 0 if R ¹¹

C 1-8 alkyl, and

The ring is a group of the formula a) wherein f

M and N together are a second bond

M is hydrogen, OH whereby B, R ^2, G, R ^3, D and E are hydrogen, and

X is an oxygen atom, two hydrogen atoms, or a hydroxyimino group of N-OH,

R ³ and D are the same or different, each hydrogen, cyano or C 1 -C 4 alkyl or together methylene or ethylene,

This hydrogen atom is a C 1 -C 4 alkyl group, D and A second bond between the C 1 and C 2 atoms is either a methylene group or

(b) a group of formula (g), or

c) a group of the formula (h) in which

R ^{11 is} hydrogen or C 1-8 alkyl.

Substituted and unsubstituted phenyl or heterocyclic groups, for example furyl, thienyl, pyridyl, pyrazolyl, pyrrolyl, pyrimidinyl, oxazolyl, pyridazinyl or pyrazinyl, can be used in the context of V.

When YR ^{4 is} hydrogen and Y 'is an ethylene substituted in the 1-position with oxo and R ^{4 is} hydrogen, Y 1 -R ^{4 is} an acetyl group which is preferred in the present invention.

The phenyl group, when monosubstituted, is in the 3-, 4- or 5-position, in case of disubstitution

4- and 5-, or 3- and 4-positions, as a fused second ring, for example, cyclohexene, pyrrole, furyl, pyrroline, 1,3-dioxacyclopentene, pyrazoline, didehydromorpholine, didehydropiperidine, didehydropiperazine, dihydropyran, pyrimidine, pyridine, pyrazine or a 1,4-dioxacyclohexene ring are preferred.

1-8 and the other contained in ^one of R 1 or 2 report, the meaning of R are composed of R ¹ and R ¹¹ and R ^2, R ^3, B, G and D is C 1-4 alkyl groups, whereby methyl ethyl, propyl, isopropyl, butyl and methyl, ethyl, propyl are preferred.

HU 210 532 A9

When R ¹² represents an acyl group, formyl, acetyl, propionyl, butyryl and benzoyl are preferred.

R ¹¹ and R ^{12 are} interrupted by a nitrogen atom to form one

They form a 5- or 6-membered heterocycle which may contain an additional 0 or S atoms in addition to nitrogen and carbon; examples of such groups are pyridine, pyrrolidine, piperidine, piperazine, morpholine, oxa and thiazolidine and thiadiazolidine.

In the formula (I), each of the alkyl, alkoxy or acyloxy groups in the formula (R ⁵⁾ and R ⁶ and R ⁷ , R ⁸ , R ⁹ , R ¹⁰ and U is 1-4 in addition to carbon, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy, isopropoxy, formyl, acetyl, propionyl and isopropionyl are preferred. Among the alkenyl groups, R ⁶ is propenyl and butenyl, which may be of the E 2 or Z configuration, i.e. when R ^{6 is} -CH = CH- (CH ₂ ) _k CH ₂ -R ⁹ , k is preferably 0 or 1.

The novel compounds of formula (I) are prepared by the process of claim 14.

For the preparation of intermediates of formula (II) wherein R ^{1 is} methyl or ethyl, it is 1 or 2,

A blocked keto group in the form of K ketal or thioketal, and

V 'is a phenyl group of formula (i) or a 5- or 6-membered heteroaromatic ring of formula (j) containing 1 to 2 N, O or S atoms in the latter

Fish with fluorine, chlorine, bromine or iodine,

R ^4a , R ^4a , Y'a and Y ' ^a other than cyano R ⁴ ,

R ⁴ ', Y and Y' have the same meaning, but the hydroxy, mercapto, amino, oxo or terminal acetylene groups which may be present are protected, which compounds are also encompassed by the invention, for example EP-A0110434, DE-A. Starting from the epoxide (ΠΙ) obtained as described in EP-A-0127864 or

R ¹ , 1 and K are as defined above.

The above epoxides are coupled by the addition of Grignard (Tetrahedron Letters 1979, 2051) to the arylmethyl halides of formula (V), wherein Hal is a chlorine, bromine or iodine atom, and the aromatic compound (carbocyclic or heterocyclic) is position on the methyl group has a fluorine, chlorine, bromine or iodine atom to give the intermediates of formula (Π) according to the invention.

After protecting the functional groups that may be present in V ', the new compounds of formula II are cyclized.

The hydroxy, mercapto and keto protecting groups in V 'and K are readily cleaved groups in acidic media, such as methoxymethyl, ethoxymethyl, tetrahydropyranyl, ethylenedioxy-ketal, ethylene-dithiocetal or 2,2- dimethyl trimethylene ketal ketal.

Suitable protecting groups for amino and terminal acetylene groups (such as trimethylsilyl and tert-butyldimethylsilyl) are known to those skilled in the art and can be removed in the desired reaction sequence by methods known in the art [Synthesis 1980, 627, J. Org. Chem., 46, 2280 (1986)],

Conversion of a compound of formula (II) to a new steroid of formula 19,11-β-bridged (IVb) wherein R ¹ , K and 1 are as defined above and V is the same as V, with V being optionally the hydroxy, mercapto, amino, oxo and / or terminal acetylene groups present and which are also subject to the present invention when the α-halogen substituent in V 'is bromine or iodine in a manner known per se ( Tetrahedron Letters 1982, 2575; 1985, 6001; 1986, 2833; J. Am. Chem. Soc. 1982, 104, 2321; Radicals in Organic Synthesis: Formation of Carbon-Carbon Bonds, Pergamon Press 1986), by reductive radical cyclization.

For aromatics substituted by fluorine and chlorine, the appropriate method has not been known so far. It has been found that these cyclizations are carried out in a good yield, surprisingly, with the starting material mixed with an electropositive metal such as sodium, potassium, lithium or calcium in one or more suitable organic solvents such as diethyl ether, dimethoxyethane (DME), dioxane or tetrahydrofuran. in ammonia at -100 to -30 ° C, preferably -78 to -60 ° C. The fact that these cyclizations can also be accomplished with the fluoride ion leaving group is particularly surprising.

This new process is also used for bromine and iodine substituted aromas.

The cyclization product thus obtained to the final desired final product of formula (I) is analogously known in the art (e.g., J. Fried, J. Edwards, "Organic Reactions in Steroid Chemistry", Van Nostrand Reinhold Company 1972.1 and 2; Steroids' Specialist Periodical Report, The Chemical Society, London, Volumes 1-12), according to which

a) oxidizing the C-17 hydroxy group and then

b) removing the protecting group from the hydroxy optionally having a protecting group in V ', optionally preparing the corresponding C 1 -C 4 perfluoroalkyl sulfonate, optionally the perfluoroalkyl sulfonate or the perfluoro, in the hydroxy compound; converting the alkylsulfonate leaving group to a tin-trialkyl group by converting it to the corresponding tin-trialkyl compound to give the desired substituent groups in V, optionally after further reactions, or first under b) and then under a) and then

c) forming the substituents on the ring D as desired in a manner known per se, treating the product thus obtained with a dehydrating agent which is also capable of liberating the 3-oxo group, simultaneously forming a 4 (5) double bond while removing water; or Z substituents temporarily

Re-protect the functional groups liberated by A9 by introducing the desired groups into the A and B rings of the steroid backbone, or

d) treating the resultant product with a dehydrating agent which is also suitable for liberating the 3-oxo group, simultaneously forming a 4 (5) double bond while cleaving the water, introducing the desired substituents into rings A and B of the steroid skeleton; after protecting the oxo group, the D ring is provided with the desired groups or the steps a) and b) are carried out after steps c) and d), the product thus obtained is optionally deprotected, optionally with the hydroxymercapto present in V; and / or alkylating and / or acylating the amino groups, optionally introducing a cyano group into the aryl group (s), optionally oxidizing the amino and / or sulfide groups optionally present in the aryl substituents, optionally converting it with hydroxylamine hydrochloride X is an N-OH hydroxyimino group and optionally a pharmaceutically acceptable salt a salable acid addition salt.

During this pathway, it may be necessary to temporarily introduce new protecting groups into the intermediate, for example, in the case of the functional groups present in Z, before the formation of the functional group in the A and B rings or in the 3-keto group before the D ring.

Steps for the preparation of almost all the final product, oxidation of the N-hydroxy group, are carried out in a manner known per se, for example by Oppenauer oxidation or chromic acid reagent (Jones' reagent or chromic acid pyridine).

The 3-keto group is liberated by simultaneous digestion of water and formation of the 4 (5) double bond by treatment with an acid or an acidic ion exchanger. The acidic treatment is carried out in a manner known per se by dissolving the appropriate 5a-hydroxy-3-ketal in a water miscible solvent such as aqueous methanol, ethanol or acetone and catalytic amounts of mineral or sulfonic acid such as hydrochloric acid, sulfuric acid, perchloric acid or reaction with toluenesulfonic acid, or with an organic acid such as acetic acid, until the protecting group is removed and, where appropriate, water is cleaved. The reaction, which takes place at temperatures between 0 and 100 ° C, may also be carried out with an acidic ion exchanger. The progress of the reaction can be monitored by analytical methods such as thin-layer chromatography of the sample taken.

Generally, deprotection and water deprotection can be accomplished in a reaction vessel by reacting the appropriate 5α-hydroxy-3-ketal and 5-ene-3-ketal in a strongly acidic medium for a period of time as described in Example le). However, it is equally good, and it is possible, according to the invention, for the protecting group and the water deprotection to be carried out in two separate reaction steps, firstly treating the corresponding 5a-hydroxy ketal in a strongly acidic medium for a shorter period. , and optionally isolated as shown in Example 9. The 5a-hydroxy-3-keto compound is then converted to the 3-keto-4-ene compound by further acid treatment,

A particular advantage of the present invention is the wide variety of substituents that can be introduced into carbocyclic or heterocyclic V aryl groups (M. Pereyre, J.-P. Quintard, A. Rahm, Tin in Organic Synthesis; Butterworths, 1987). For example, the R ⁴ -Y or R ⁴ '-Y' substituents present in the final products may be introduced directly by the corresponding arylmethyl halide of formula (V) substituted with an aryl group by a suitable compound of formula 5a, 10a (ΙΠ). epoxide by a Grignard reaction and the resulting intermediate of formula (II) is worked up as described above.

The number of Vn substituted compounds that can be produced in this way is relatively limited because not all of the desired substituents in the final product can withstand the conditions of the Grignard reaction with V'CH ₂ Hal with 5a, 10a-epoxide (III). and, in particular, the reductive conditions used to convert the intermediate of Formula II to the 19.11 β-bridged steroid of Formula IV cannot be sustained without damage.

However, in a further embodiment of the methods of the invention, the substituents on the V aryl group are more widely varied. Accordingly, the substituents are introduced only after the cyclization and prior to, at the same time, or only after the complete structure of the A, B and D rings. For this, at least one of the hydroxy groups present and protected in the V and V groups must be liberated and from the free hydroxy group by perfluoroalkylsulfonic anhydride (the alkyl group having 1 to 4 carbon atoms) in a manner known per se [P. J. Stang, M. Hanack, and L. R. Subramanian, Synthesis 85 (1982)] to provide the corresponding perfluoroalkyl sulfonate compound. This is achieved either by converting the perfluoro-transition group into a desired substituent or its precursor in a reaction catalyzed by a transition metal (preferably Pdo) (JE Mc Murry and S. Mohanraj, Tetrahedron Letters, 24 (27)). , 2723-2726, 1983; C. Lu and J. Zhu, Communications, 726-727 (1987), Q.-Y. Chen and Z.-Y. Yang, Tetrahedron Letters 27 (10), 1171-1174 (1986). S. Cacchi, PG Ciattini, E. Morera and G. Ortar, Tetrahedron Letters, 27 (33), 39313934 (1986), AM Echavarren and JK Stille, J. Am. Chem. Soc. 1987, 109, 5478-7. 5486) or the perfluoroalkylsulfonate compound from the intermediate and using a transition metal catalyst to prepare a suitable tri (organyl) stannyl, preferably tri (n-alkyl) stannyl, CJ. K. Stile, Angew. Chem. 98, 504-519 (1986)], This is then followed by a single reaction with a carbocyclic or heterocyclic aromatic compound substituted with a halogen atom, preferably bromine or iodine [Y. Yamamoto, Y. Azuma, H. Mitoh, Communications, 564-565, 1986; T. J. Bailey, Tetrahedron Letters, 27 (37), 4407-4410 (1986), which may optionally carry additional substituents, a 19,11β4

HU 2105322 A9 is converted to a bridged steroid; the V and V aryl groups are then substituted with the desired or preceding substituents.

The intermediate tri (n-alkyl) stannyl compound can also be isolated, as in Example 39a) a), 11β, 19- [4-tri (n-butyl) -stanyl-offenylene] -3,3- ( 2,2-Dimethyltrimethylenedioxy) androstane5α, 17β, 4β1.

The introduction of 1,2- and / or 6,7-double bonds in addition to the 3,4-double bond is known in the art with a dehydrating agent such as selenium dioxide, chloranil, thallium triacetate or dichlorodicyanobenzoquinone (DDQ) or allyl or dienol ether bromination and subsequent hydrobromide cleavage [J. Fried, J. A. Edwards, Organic Reactions in Steroid Chemistry, Van Nostrand Reinhold Company 1972, 265-374, 1; Tetrahedron 42, 2971 (1986). For example, allyl bromination is carried out in a solvent in the presence of N-bromosuccinimide, N-bromoacetamide, 1,3-dibromo-5,5-dimethylhydantoin or dibromotetrachloroethane, such as dibenzoyl peroxide. Suitable solvents are aprotic solvents such as dioxane and chlorinated hydrocarbons such as carbon tetrachloride, chloroform or tetrachlorethylene. The reaction is carried out at a temperature between 0 ° C and the reflux temperature of the solution.

The dienol ether bromination is carried out analogous to that described in Steroids I, 233.

Hydrogen bromide is cleaved during the formation of the delta ^6- double bond by treating the 6-bromo compound with a basic agent, preferably lithium bromide and lithium carbonate or lithium bromide and calcium carbonate in an aprotic solvent such as dimethylformamide 50 and 120. The reaction mixture is heated at a temperature of from about 0 ° C. A further possibility of cleaving HBr is by heating the 6-bromo compound in collidine or lutidine.

Starting from a saturated ring A, the 1,2- and 4,5-positioned double bonds can be simultaneously formed, for example, by bromination to form 2,4-dibromo-3-ketone, and the dibromide with, for example, lithium or calcium carbonate and lithium bromide in dimethyl dehydrobrominated in formamide.

The introduction of the 6-methyl group, for example, starting from a 3-amino3 (4), 5 (6) -diene derivative by reaction with my forms in an alcoholic solution [Helv. Chim. Acta, 56, 2396 (1973)) followed by cleavage of the 6a-hydroxymethyl group in an acidic medium such as hydrochloric acid in dioxane-water or a 3-alkoxy-3 (4), 5 (6)-diene derivative. U.S. Pat. No. 4,544,555, or directly starting from a 3-oxo-4 (5) ene derivative, is similar to that described in Synthesis (1982) 34.

The methylation of the 6-methylene compound to the 6,6-ethylene compound is carried out with dimethylsulfoxonium methylide. To this is added the 6-methylene steroid to a suspension of trimethylsulfoxonium iodide and sodium hydride in mineral oil with dimethylsulfoxide or a solution of trimethylsulfoxonium iodide and sodium hydroxide in dimethylsulfoxide. The reaction is carried out at a temperature of 20 to 40 ° C for 15-60 minutes [J. Chem. Soc., 84, 866 (1962); European Patent Application 0150157).

The introduction of the 2-methylene group by A. J. Manson and D. Wood in J. Org. Chem., 32, 3434 (1967), and cited therein.

The methylation of the 2-methylene compound to the 2,2-ethylene compound is carried out as described for the methylation of the 6-methylene compound. still Chem. Bér. 98: 1470 (1965)].

The 2-position mono- or dialkylated compounds can be obtained, for example, by the method of L. Nedelec (Tetrahedron 30, 3263 (1974)).

Alkylated compounds at the 1- and 7-positions by 1,4- and 1,6-addition to the corresponding enone are known in the art [J. Fried, J. A. Edwards: Organic Reactions in Steroid Chemistry, Van Nostrand Reinhold Company 1972, 75-82. 2, and J. Am. Chem. Soc., 99, 1673 (1977).

6-position alkylated compounds can be obtained, for example, by opening the corresponding 5a, 6a-epoxide and subsequent reaction [J. Fried, J. S. Edwards: Organic Reactions in Steroid Chemistry, Van Nostrand Reinhold Company 1972, 82-86. 2].

Ια, 2α, 6a, 7α, 6β, 7β-Methylene compounds or combinations of the 1a, 2a-methylene moiety with both 6,7-methylene moieties by addition of diazomethane or dimethylsulfoxonium methylide to the corresponding enon or by the Simmons-Smith reaction of the appropriate allyl alcohol [J. Fried, J. A. Edwards: Reactions in Steroid Chemistiy, Van Nostrand Reinold Company 1972, 100-126. side; Port. Soc. Quim. Mex. 171A (1969); Chem. Bér. 101: 935 (1968); Chem. Bér. 99, 1118 (1966); Zeitschr. f. Naturf. 19b, 944 (1964)].

The isoxazole ring annealed at the 2- and 3-positions is a

2-hydroxymethylene (Steroids 6: 178, 1962); Chem. Soc., 83, 1478 (1961)] and reaction of the resulting compound with hydroxylamine [J. Med. Chem. 6 (1963) 1].

[2,3-d] Isoxazoles are also good starting materials for the synthesis of 2-cyano-steroids [J. Med. Chem. 6 (1963) 1]. The pyrazole rings annealed at the 2- and 3-positions are prepared by reacting the 2- (hydroxymethylene> 3-oxo) starting material with R ^n- substituted hydrazine (U.S. Pat. No. 3704295).

The position of the steroid skeleton at the C6 position is, for example, following the methods of chlorine or methyl as disclosed in German Patent Publication No. 1,158,966 and U.S. Patent Nos. 4,544,555 and 4,196,203, respectively.

It is introduced via the 6-methylene derivative and by the oxidation of 6-chloro-3,5-dienol ethers in dichlorocyanobenzoquinone (DDQ) in acidic medium (Belgian Patent No. 621,197, 1962).

The 3-oxo group may be removed by thioketalization and subsequent reductive cleavage to produce the final product of formula (I) wherein X is two hydrogen atoms, for example, according to the procedure described in DOS 2805490.

HU 210 532 A9

Compounds containing the D-homo-steroid backbone are obtained, for example, by the Tiffeneau rearrangement as described in Australian J. Chem., 8, 1955, 519 and Organic Reactions in Steroid Chemistry, 2, 388. The required 17α-aminomethyl-17β-hydroxy compounds are prepared, for example, by opening the 17,20-spiroepoxide with ammonia or by subjecting the acetylated 17β-hydroxy-17α-cyano compound to lithium aluminum reduction. The reaction of spiroepoxides with the corresponding 17-ketone and dimethylsulfonium methylide in dimethylformamide [Journal f. pract. Chemie 314: 667-668 (1972). Acetylated cyanohydrin by addition of hydrogen cyanide to the corresponding 17-ketone and subsequent acetylation is known in the art. for example, Australian J. Chem., 8, 519 (1955)).

The starting materials containing the unsaturated D ring can be prepared, for example, by modification of the Saegusa oxidation (Tetrahedron 42, 2971 (1986)) with the corresponding 17-ketone enol. For example, the 17-ketone is converted to the corresponding enolate with lithium diisopropylamide in tetrahydrofuran and the enolate is reacted with trimethylchlorosilane (Synthesis 1983, 1) to give the trimethylsilyl enol ether.

The substituents R ⁵ and R ⁶ are introduced by nucleophilic addition to the C-17 side chain, e.g. Chemical Society, London, Vol. 1-12).

Substituent introduction, in ⁶ representing R -C = CU formula wherein U is using the above, a MCSC-yl, compound of formula happen U in this formula, a protecting group such as trimethylsilyl or tert-butyldimethylsilyl -Silyl-protected U, or, if U is C 1-4 alkyl, U 'has the same meaning as U.

The organometallic compound can also be formed in situ and reacted with the 17-ketone. For example, 17-ketone is reacted in a suitable solvent with acetylene and an alkali metal, in particular potassium, sodium or lithium in the presence of an alcohol or ammonia. The alkali metal may be, for example, in the form of methyl or butyllithium. Particularly suitable solvents are dialkyl ether, tetrahydrofuran, dioxane, benzene and toluene.

The 17-ketone is introduced into the 17-position of the 3-hydroxypropine, propene or propane group by contacting the 17-ketone with the dianion of propargyl alcohol (3-hydroxypropine), for example, from the dipotassium salt of propargyl alcohol. with a dianion liberated in situ to a 17α- (3-hydroxyprop-1-ynyl) -17β-hydroxy derivative or a metal derivative of 3-hydroxypropine such as 1-lithium-3- (tetrahydropyran-2-yloxy) prop-1-yn. With 1 -ide it is converted to the 17- [3- (tetrahydropyran-2'-yloxy) -prop-1-ynyl] -17β-hydroxy derivative and then 17- (3-hydroxypropyl or hydroxypropenyl) -17β-hydroxy hydrogenation. The hydrogenation is carried out, for example, at room temperature and at normal pressure in a solvent such as methanol, ethanol, propanol, tetrahydrofuran or ethyl acetate in the presence of a noble metal catalyst such as platinum or palladium.

Homologous hydroxyalkine, hydroxyalkene and hydroxyalkane groups are similarly formed using homologues of propargyl alcohol.

The compound containing the Z-configuration double bond in the hydroxypropenyl group is a deactivated noble metal catalyst in acetylene triple bond (J. Fried, J. Edwards, Organic Reactions in Steroid Chemistry, 1974, Van Nostrand Reinhold Company, p. Hydrogenation in the presence of Modem Synthetic Reactions (1972, p. 19). Deactivated noble metal catalysts include, for example, a 10% palladium catalyst supported on barium sulfate in the presence of an amine or a 5% palladium on calcium carbonate addition of lead (II) acetate. The hydrogenation is terminated after uptake of one equivalent of hydrogen.

In the hydroxypropenyl group, an E-configuration double bond is formed when the acetylene triple bond is reduced in a manner known per se. There are a number of methods in the literature for converting alkynes to trans-olefins, for example with sodium in liquid ammonia [J. Chem. Soc. 63, 2141 (1941)] with sodium amide in liquid ammonia (J. Chem. Soc. 1955, 3558), with lithium in low molecular weight amines [J. Chem. Soc. 77, 3378 (1955)], borane [J. Chem. Soc., 93, 3395 and 94, 6560 (1972)], diisobutylaluminum hydride and methyl lithium [J. Chem. Soc. 89, 5085 (1967)] and especially with the lithium aluminum hydride / alcoholate system [J. Chem. Soc. 89, 4245 (1967). Further reduction of the triple bond is possible in the presence of water or dimethylfomamide in a slightly acidic medium with chromium (II) sulfate reduction [J. Chem. Soc., 86, 4358 (1964)] and, in general, reduction of the transition metal compounds during their change in oxidation state.

The hydroxyalkene group may be directly introduced into a corresponding metal-derived hydroxyalkenyl compound such as 1-lithium-3- (tetrahydropyran-2'-yloxy) -prop-1 (E) -ene (J. Org. Chem. Chem. 40, 2265) or by addition of 1-lithium-3- (tetrahydropyran-2-yloxy) -prop-1 (Z) -ene (Synthesis 1981, 999). Homologues can be prepared in the same manner.

The introduction of the 3-hydroxypropane group at the 17-position is similarly direct with the metal derivatives of the 17-ketone 3-halopropanols in which the hydroxy group after the metal conversion step is in its alcohol (Tetrahedron Letters 1978, 3013) or protected form (J. Org. Chem. 37, 1947) can be obtained by converting it to a 17- (3-hydroxypropyl) -17β-hydroxy compound or a protected compound on the terminal hydroxy group. Examples of protecting groups include ethoxyethyl, tetrahydropyranyl and methoxymethyl.

In order to obtain (I) final product of formula I wherein the radical R ⁵ / R ⁶ (c), the 17- (3-hydroxypropyl) compound ön6

EN 210 532 A9 is oxidized in a manner known per se, for example with Jones' reagent, bamako, pyridinium dichromate, pyridinium chlorochromate, chromic acid pyridine system or silver carbonate / celite Fethizone reagent [Compt. order. 267: 900 (1968).

The final products of formula (I) wherein R ⁵ / R ⁶ is (b) may be obtained by ring closure of the corresponding 17 (3-hydroxyprop-1 (Z) -enyl) -17β-hydroxy compounds.

The 17-cyanomethyl side-chain can be formed in a manner known per se, for example by converting the 17-ketone to 17-spiro-epoxide and then cleaving the spiro-epoxide with hydrogen cyanide. Chem., 18, 259-260 (1978).

The introduction of the 17-hydroxyacetyl side chain is also known in the art, for example, in J. Org. Chem. 47 (1982), 2993-2995, Chem. 113, 1184 (1984) or by the method disclosed in United States Patent 4,600,538.

The groups (k) and (1) are formed by converting the ketone to 17-nitrile with tosylmethyl isocyanide (Chem. Ind. 1972, 213) (Tetrahedron, 31, 1975, 2151), from which lithium or methyl magnesium bromide directly gives the 17-acetyl compound, which is enolized with potassium tert-butylate in tetrahydrofuran and then converted to the desired 17α-methyl-17β-acetyl group with methyl iodide. This series of methyl addition to the nitrile and subsequent alkylation can also be performed in reverse order.

The free hydroxy or the hydroxy, mercapto and / or amino groups present in the Z and V substituents may be alkylated or acylated in a manner known per se.

The sulfide and / or dialkylamino group in the V substituent with the appropriate oxidizing agent (e.g., hydrogen peroxide or peracid) to the desired sulfoxide (n = 1), N-oxide (n = 1) [see, e.g., Contact (Darmstadt) 1986, 3, p. ] or sulfone (n = 2).

In V, compounds containing a dialkylamino group in an aprotic solvent such as dioxane, benzene or toluene with bromocyano at elevated temperature (Braun's amine degradation) are described in Org. Reactions 7.189 (1953), KW Bentley, Techniques of Organic Chemistry 11, 773 (1963) and Houben Weyl, 5/4, 151 (1960) with good yields of the corresponding (N-cyano-N-alkylamino) ) -aryl derivative.

These are converted to the corresponding dialkylamino compounds (e.g. diisobutylaluminum hydride in toluene, N-formyl-N-alkylaminophenyl intermediate and then lithium aluminum hydride) and NH in accordance with the last desired meaning of R ^{12 in the} final product. It can be reduced to N-alkyl compounds (e.g. lithium aluminum hydride or lithium in liquid ammonia). These latter groups are then optionally acylated by methods known in the art and optionally reduced in a manner known per se, such as lithium aluminum hydride, to a new dialkylamino derivative (see DE 3623038).

The resulting compounds of formula (I) wherein X is oxygen, optionally in the presence of a tertiary amine with hydroxylamine hydrochloride at +40 ° C, to an oxime (a compound of formula (I) in which X is -N-OH are hydroxyimino and color or anti-position). Suitable tertiary bases include trimethylamine, triethylamine, pyridine, idin, Ν-dimethylaminopyridine, 1,5-diazabicyclo [4.3.0] nonene-5 (DBN) and 1,5-diazabicyclo [S.4.0 ] undecene-5 (DBU), of which pyridine is preferred.

The novel compounds of formula (I) and their addition salts with pharmaceutically acceptable acids are valuable drugs. They have a potent effect on the gestagen receptor and have surprisingly high levels of gestagen, antigen, antigen glucocorticoid, antimineral corticoid and antiandrogen. These important biological effects can be used for therapeutic purposes.

Such highly antigenic agents are capable of inducing abortion by depressing the receptor for progesterone, which is necessary for maintaining pregnancy. They are therefore valuable and interesting for use in postpartum contraception.

They can also be used to induce hormonal disorders such as menstruation and childbirth.

They can also be used to treat hormone dependent carcinomas.

The compounds of formula (I) of the present invention and their addition salts with pharmaceutically acceptable acids also exhibit anti-glucocorticoid activity and are thus useful in the treatment of corticoid-induced disorders such as glaucoma and in combating side effects that result from prolonged treatment with glucocorticoids. (Cushing's syndrome). They are therefore also suitable for combating glucocorticoid over-excretion, in particular obesity, arteriosclerosis, hypertension, osteoporosis, diabetes and insomnia.

The gestagenic compounds of the invention of the formula I and their addition salts with pharmaceutically acceptable acids include, for example, menstruation, menstrual disorders, excessive menstruation and yellowing deficiencies, and antimeric alkaloidic compounds which are useful in treating hypertensive conditions.

The antiandrogen compounds of the present invention and their salts with pharmaceutically acceptable acids are useful in the treatment of overgrowth and prostate cancer. These compounds can also be used for the specific therapy of androgenization phenomena in women; Thus, pathological hair growth, androgenetic baldness, as well as acne and seborrhea, can be favorably influenced by increased sebaceous gland function.

Thus, the invention is pharmaceutically acceptable, i. E., Non-toxic in the dose administered, of compounds of formula (I) and pharmaceutically acceptable.

Also included are pharmaceutical compositions containing their addition salts with acetic acids, optionally in the presence of conventional excipients and carriers.

The compounds of the present invention and their salts can be converted into enteric, percutaneous, parenteral or topical formulations by known galenic methods. They can be administered in the form of tablets, dragees, gelatin capsules, granules, suppositories, implants, injectable sterile aqueous or oily solutions, suspensions or emulsions, ointments, creams and gels.

The active ingredients are formulated with customary pharmaceutical excipients such as gum arabic, talc, starch mannitol, methylcellulose, lactose, surfactants such as Tween R or Myrj R, magnesium stearate, and aqueous or non-aqueous carriers, paraffin derivatives, , emulsifying, preserving and flavoring agents may be mixed with flavoring agents such as essential oil.

The invention thus relates to pharmaceutical compositions comprising as active ingredient at least one compound of the invention or a pharmaceutically acceptable acid addition salt thereof.

Acid addition salts of the products of the invention include, in particular, hydrochloride and methanesulfonate.

One dosage unit is approx. It contains 1-100 mg of active ingredient. The dose of the compounds of the present invention in humans is about 10 mg / kg. 1-1000 mg / day.

The antigenic activity was determined by the abortion effect.

The experiments were carried out for approx. It was performed on female rats weighing 200 g. After mating, the beginning of pregnancy was confirmed by detecting sperm in the vaginal smear. The day of sperm detection was considered as day 1 of pregnancy (dl p. C.).

Animals were challenged with the test substances or solvents following embedding of blastocytes in sections 5-7. day (d5 p.c. to d7 p.c.). On day 9 of pregnancy, the animals were sacrificed and the bees examined for embedding and resorption sites. A photograph of each bee was taken. Lack of implantation, pathological, bleeding or otherwise abnormal implantation site was assessed as abortion. .

The test substances were dissolved in a 1: 4 by volume mixture of benzyl benzoate and castor oil. The volume of vehicle for each dose was 0.2 ml. Treatment was given subcutaneously.

The preferred compounds of the invention are 17α- (prop-1-ynyl) - N -hydroxy-11β, 19 - [(4- (dimethylamino) -o-phenylene) -4-androsten-3-one (A). ), 17α- (propyl-inyl) -17β-hydroxy-11β, 19- (4-acetyl-o-phenylene) -4-androsten-3-one (B), 17α- (3-hydroxypropyl), 1 (Z) -enyl) 17β-hydroxy-11β, 19- [4- (dimethylamino) -o-phenylene) -4-androsten-3-one (C), 17α- (3-hydroxyprop-1- (Z) -enyl) 17β-hydroxy-11β, 19-C4- (methylthio) -o-phenylene) -4-androsten-3-one and 11β-C4- (dimethylaminophenyl) disclosed in European Patent Application 0057115. ) -17? -Hydroxy-17? - (propin-1-yl) -4,9 (10) -estradien-3-one (E); -phenyl] -17β-1ιί0Γθχΐ-17α- (3-hydroxyprop-1- (Z) -enyl) 4,9 (10) -estradien-3-one (F).

Table 1 shows that only Compounds A-D of the invention and Compound F have a complete abortion effect at 1.0 mg subcutaneously. Comparative substance E shows only a 50% effect at this dose. Compound B according to the invention is fully effective even at a subcutaneous dose of 0.3 mg, while Compound F is no longer effective at this dose.

Table 1

Abortion testing in pregnant rats Treatment of pregnancy 5-7. day, autopsy on day 9

Vegyidet Dose in mg / animal / day s. c. Abortion rate n abortion / η total % THE 3.0 4/4 4/4 1.0 4/4 100 0.3 1/4 25 B 3.0 4/4 100 1.0 4/4 100 0.3 4/4 100 C 3.0 4/4 100 1.0 4/4 100 0.3 0/4 0 D 3.0 4/4 100 1.0 4/4 100 0.3 1/4 25 E 3.0 4/4 100 1.0 2/4 50 F 3.0 4/4 100 1.0 4/4 100 0.3 0/4 0 Solvent as a control: 0.2 ml benzyl benzoate + castor oil (1 + 4) - 0/5 0

n = 4 rats

For the evaluation of the anti-glucocorticoid activity, 17α-3-1ΰ0Γθχΐ-ρΓορ-1 (Ζ) -εηΐ1) -17β-hydroxy-11β, 19- [4- (dimethylamino) - represented by all the compounds of formula I according to the invention The anti-thymolytic activity of o-phenylene] -4-androsten-3-one (C) in the rat was investigated, and the result was again compared with that of comparators E and F.

In rats, glucocorticoids exert their effects on the kidney8

A massive increase in the mass of the thyroid gland (thymolytic effect) occurs. Inhibition or elimination of glucocorticoid-induced thymus suppression is expected when glucocorticoid antagonists are administered.

The experiments were performed on juvenile male rats (100-130 g) from which the adrenal gland was surgically removed. The housing conditions were traditional, with the illumination rhythm: 10 hours darkness, 14 hours light; the average temperature is 20 + 2 ° C; standard rat diet (pellets); the tap water and 0.9% sodium chloride solution were supplied from a separate drinking glass.

For subcutaneous administration, the material was dissolved in a 1: 4 by volume mixture of benzyl benzoate and castor oil, and the respective daily dose was injected in 0.2 ml vehicle volume. Selected doses are shown in Table 2.

Dexamethasone was used as the glucocorticoid standard substance at 0.01 mg / animal / day s.c. doses. This dosing, including solvent control, resulted in approximately 75% reduction in thymus weight. The solvent was a 1: 4 v / v mixture of benzyl benzoate and ricinul oil in a daily volume of 0.2 ml.

About 5 days prior to treatment, the animals were anesthetized and the adrenal glands were removed. The assignment to different study groups was possible; the number of animals tested is also shown in Table 2. Treated groups: Dexamethasone control solvent control test substance dose + dexamethasone.

The treatment lasted 4 days. On day 5, the animals were sacrificed with carbon dioxide. Thymus weight was determined and mg / 100 g body weight was calculated.

The difference between the solvent control and the dexamethasone control (0.01 mg / animal / day s.c.) was taken to be 100% to assess the anti-glucocorticoid activity of the test substance. Measured values were then calculated from the mean% antigen glucocorticoid activity (% abolition of dexamethasone-induced thymus suppression) using the following formula:

⁵ MWs-MWrv ^

MW1-MW ^ '

In the formula

MW _S = substance dose + dexamethasone η

MWp _exa = for dexamethasone

MEs = mean value for the solvent control mean group

As shown in Table 2, Compound C is the highest tested, 30.0 mg / d s.c. dose, dexamethasone-induced thymus suppression was negligible. Lower, 3.0 and 10 mg / d s.c. no doses of antiglucocorticoid were observed at doses.

Compared to Compounds Ε (Figure 2) and F (Figure 1), we also found that the antigen glucocorticoid activity of Compound C is rather low.

EP-A-0188396 discloses structurally similar steroids having a 10-substituted aryl group and a 9 (II) double bond; however, these known compounds are in each case substituted at the 17a position by alkyl, alkenyl or alkynyl. However, these compounds exhibit considerable anti-glucocorticoid activity, while their activity against the progesterone receptor and thus their antigenic activity is negligible.

Thus, the compounds of the present invention provide substances that exhibit a novel activity profile in the art, namely, a significantly increased antigenic activity and only moderate antiglucocorticoid activity.

Table 2

Determination of Antiglucocorticoid Effect by Thymolysis Assay Elimination of Dexamethasone-Induced Thymus Suppression (Male rats weighing 100-130 g and adrenal gland were surgically treated for 4 days, dissected on day 5)

Dexamethasone Compound C (mg / d s. C.) Relative thymic weight n (mg / 100 g body weight) M ± SD Cancellation% the) - - 7 361.0 ± 51.5 0.01 - 7 77.4 ± 7.8 0.01 3.0 7 72.4 ± 10.9 -1.8 (-12,1-7,5) 0:01 10.0 7 76.9 + 6.6 -0.2 (-10,4-9,1) 0.01 30.0 7 125.0 ± 16.4 16.8 (7.5 to 25.5) the) - - 12 419.8 ± 61.9 0.01 - 12 91.2 ± 16.6 0.01 3.0 6 110.6 ± 16.3 5.9 (-4,1-15,4) 0.01 10.0 6 194.4 ± 27.9 31.4 (22.1 to 40.5) 0.01 30.0 6 197.3 ± 49.6 32.3 (23.0 to 41.3)

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Dexamethasone Compound C (mg / d s. C.) Relative thymic weight n (mg / 100 g body weight) M ± SD Cancellation% the) - - 24 385.4 ± 51.3 0.01 - 18 87.2 ± 13.2 0.01 3.0 6 125.6 ± 19.9 12.9 (0.5 to 24.6 0.01 10.0 6 178.1 ± 44.8 30.5 (18.6 to 42) 0.01 30.0 6 264.7 ± 41.0 59.5 (48.0 to 71.0)

a) Control group: Benzyl benzoate: Castor oil - 1: 4, 0.4 ml / d s.c. () 95% safety margin of elimination n is the number of animals tested

Figure 1

Effect of selected subcutaneously administered compounds on dexamethasone-induced thymus suppression in male rats weighing 100 to 130 g, with adrenal glands surgically removed

Treatment time: 4 days (dose mg / d)

Thymic mass was determined on day 5,

(): number of rats in each group: 95% confidence interval for% elimination rel.thymus: relative thymus weight (mg / 100 g body weight)

Abolition: Corticoid Abolition Compound C: Compound Compound F: F

Figure 2

Effect of selected subcutaneously administered compounds on dexamethasone-induced thymus suppression in male rats weighing 100 to 130 g, with adrenal glands surgically removed

Treatment time: 4 days (dose mg / d)

Thymic mass was determined on day 5.

(): number of rats in each group: 95% confidence interval for% elimination rel.thymus: relative thymus weight (mg / 100 g body weight)

Abolition: elimination of the corticoid effect

Compound C: Compound C

Comeound Ε: E compound

In the following examples, unless otherwise noted, chromatography is carried out with a mixture of ethyl acetate and hexane.

Example 1

17-hydroxy-11,19- (o-phenylene) -4-androsten-3-one (o-19-2-chlorophenyl-3,3- (2,2-dimethyltrimethylenedioxy) - II -andostene-5a, 17 $ -diol 4.9 g of magnesium turnings were placed in 40 ml of absolute diethyl ether under shielding gas, followed by 0.5 ml of 2-chlorobenzyl chloride and then carefully 0.4 ml 1,2-Dibromoethane is added and after the reaction is complete, the remaining amount of 2-chlorobenzyl chloride (18.4 mL) is dissolved in 135 mL of absolute diethyl ether over a period of 40 minutes without dropping to 30 ° C. Do not rise above 60. After completion of formation of the Grignard reagent, the reaction mixture is cooled to 0 ° C and 13.6 g of 5a, 10aepoxy-3,3- (2,2-dimethyltrimethylenedioxy) -9 ( ) - A solution of estrene-17? -ol in 75 ml of absolute tetrahydrofuran is slowly added dropwise and the reaction mixture is stirred for one hour at ice-cooling temperature and then slowly overnight at room temperature. The reaction mixture was heated to reflux and then poured into dilute ammonium chloride solution and the aqueous phase was extracted several times with ethyl acetate. The combined organic phases were washed neutral with brine, dried over sodium sulfate and concentrated in vacuo. The residue was chromatographed on alumina (neutral, activity III). 14.8 g of the title compound are obtained.

[α] D = -2 ° (CHCl ₃ , c = 0.51)

188-191 ° C (ethyl acetate)

b) 11 β, 19- (o-Phenylene-3,3-2,2-dimethyltrimethylenedioxy) androstane-5α, 17 β-diol

At -65 [deg.] C., 600 ml of anhydrous ammonia were condensed into the reaction flask with the exclusion of moisture and 970 mg of freshly cut lithium shavings were added. After the appearance of a characteristic blue coloration, a solution of 14 g of the product obtained in step a) in 450 ml of absolute tetrahydrofuran was added dropwise so that the color of the reaction solution and the appearance of the blue color alternate. After the addition was complete, the excess lithium was quenched by dropwise addition of ethanol, most of the ammonia was removed by evaporation, and the reaction mixture was poured into water. The aqueous phase was extracted with ethyl acetate. The combined organic phases were then washed with brine, dried over sodium sulfate and concentrated in vacuo. 13.9 g of crude product are isolated. Chromatography on alumina (neutral, ΙΠ activity) gave 10.3 g of the title compound.

[a] D = +13 '(CHC1 _3, C = 0.52)

164-167 ° C (ethyl acetate)

1 H-NMR (CDCl ₃ ) [δ]: 7.0-7.45 (4H, m, aromatic protons); 3.13 (1H, d, J = 16 Hz, C-19 linked proton); 2.68 (1H, d, J = 16 Hz, C-19 linked proton); 0.98 (protons of 3H, s, ketalmethyl); 0.95 (protons of 3H, s, ketalmethyl); 0.25 (3H, s, C-18-linked protons).

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The title compound of step b) may also be prepared in the following manner:

a) 19- (2-Bromophenyl) -3,3-2,2-dimethyltrimethylenedioxy-9 (11'-androstene-5c, 17 $ -diol)

In a similar manner to Example 1a, 5 g of 5a, 10a-epoxy-3,3- (2,2-dimethyltrimethylenedioxy) -9 (11) -estrene-17 (3-ol) were treated with 26.7 g of 2-bromobenzyl bromide. Chromatography gave 5.9 g of the title compound as a white bean.

1 H-NMR (CDCl ₃ ) [δ]: 6.95-7.55 (4H, m, aromatic protons); 5.45 (1H, broad s, proton bound to Cl1); 3.7-3.82 (1H, m, proton bound to C-17); 3.4-3.6 (4H, m, protons of ketalmethyl groups); 3.16 and 3.07 (each IH, d, at 15 Hz, Α, Β system, C-19 protons); 0.98 (3H, protons of a ketalmethyl group); 0.9 (3H, s, protons of a ketalmethyl group); 0.55 (3H, s, C-18 linked protons).

β) 1β, 19- (o-Phenylene) -3,3- (2,2-dimethyltrimethylenedioxy) androstane-5α, 17β-diol

2.5 g of the compound prepared in a) are dissolved in 250 ml of absolute toluene, 2.25 ml of tributylnehydride and 250 mg of α, α-azobisisobutyronitrile are added and the mixture is refluxed for 3 hours. The solvent was removed in vacuo and the residue was taken up in tetrahydrofuran and stirred with 50 mL of saturated aqueous potassium fluoride for 1 hour. The aqueous phase is then extracted with ethyl acetate and discarded. The organic phases are combined, dried over sodium sulfate and concentrated in vacuo. The residue was chromatographed on alumina (neutral, ΠΙ activity level). 1.75 g of the title compound are obtained.

The title compound of step b) may also be prepared from the following compound:

γ) 19- (2-Fluorophenyl) -3,3-2,2-dimethyltrimethylenedioxy-9,11-androstene-5α, 17β-diol

In a similar manner to Example 1a), 750 mg of 5a, 10aepoxy-3,3- (2,2-dimethyltrimethylenedioxy) -9 (11) -estrene-17β-ol 10 mg of 2-fluorobenzyl chloride were reacted. After chromatography, 798 mg of the title compound is isolated as a white foam.

1 H-NMR (CD ₂ Cl ₂ ) [δ]: 6.92-7.33 (4H, m, aromatic protons); 5.09 (1H, m, proton bound to C-11); 3.62-3.72 (1H, m, proton bound to C-17); 3.45-3.58 (4H, m, protons of the ketalmethylene groups); 2.97 and 2.9 (each IH, d, at 15 Hz, fission system, Α, Β system, proton bound to C-19); 0.99 (3H, s, protons of a ketalmethyl group); 0.9 (3H, s, protons of a ketalmethyl group); 0.61 (3H, protons bound to C-18).

δ 11 β, 19- (o-Phenylene) -3,3- (2,2-dimethyltrimethylenedioxy) androstane-δ 0.17 $ diol

In the same manner as in Example 1b, 750 mg of 19- (2-fluorophenyl) -3,3- (2,2-dimethyltrimethylenedioxy) -9 (II) -androstene-5a, 17-diol is reacted with 60 mg of lithium. After chromatography, 585 mg of the title compound is isolated as a white foam.

c) 17-Hydroxy-11,19- (o-phenylene) -4-dimethylene-3-one g, The product of step b) is dissolved in 100 ml of acetone and 5 ml of 4N hydrochloric acid is added. After stirring at room temperature for 4 hours, the reaction mixture was poured into saturated sodium bicarbonate solution and the aqueous layer was extracted with dichloromethane. The combined organic phases were dried over sodium sulfate and concentrated in vacuo. The residue was chromatographed on silica gel. 1.13 g of the title compound are obtained.

[a] D = + 84 ° (CHC1 _3, C = 0.5) H-NMR (CDC1 ₃₎ [δ]: 7-7.5 (4H, m, aromatic protons);

5.88 (1H, s, C-4-linked protons); 3.68 (1H, tr, J = 9 Hz, proton bound to C-17); 3.3 (1H, m, proton bound to C-11); 3.26 (1H, d, J = 17Hz, C-19 attached proton); 2.74 (1H, d, J1 = 17 Hz, proton bound to C-19); 0.29 (3H, s, proton bound to C-18).

Example 2

17-hydroxy-17- (prop-1-ynyl) -119,9-o-phenylene -4-androsten-3-one

a) 1 H, 19- (o-Phenylene) -5a-hydroxy-3,3-2,2-dimethyltrimethylenedioxydandrostan-17-one

To a mixture of 34.3 ml of pyridine and 287 ml of dichloromethane was added 11.28 g of chromium trioxide in portions at 0 ° C. A solution of 8 g of the steroid prepared in Example 1b in 50 ml of dichloromethane was then added dropwise at a similar temperature to the reaction mixture, and the mixture was stirred for an additional two hours at ice bath temperature. After stirring, the solid reaction components were allowed to settle, the supernatant was decanted and the precipitate was washed several times with dichloromethane several times. The combined organic phases were freed from the remainder of the inorganic component with 0.5 M aqueous potassium hydroxide solution, washed with water to neutral, dried over sodium sulfate and concentrated in vacuo. 7 g of crude 11 β, 19- (o-phenylene) -5α-hydroxy-3,3- (2,2-dimethyltrimethylenedioxy) androstan-17-one are obtained, the purity of which is sufficient for further reaction. (see below). Purify 500 mg by analytical purification on alumina (neutral, ΙΠ activity level). 432 mg of the desired product is isolated.

[α] D = + 31 ° (CHCl ₃ ; c = 0.505)

M.p. 206-210 ° C (ethyl acetate)

b) 17- (Prop-1-ynyl) -11,19- (o-phenylene) -3,3-2,2-dimethyltrimethylenedioxydandrostane-5-c, 17 $ -diol

225 ml of absolute tetrahydrofuran are saturated with propin at 0 ° C. Subsequently, 27.7 ml of a 1.6 M solution of n-butyllithium in hexane was added slowly, without increasing the temperature. After stirring for 15 minutes, a solution of the crude product of step a) in 45 ml of absolute tetrahydrofuran is added slowly dropwise to the reaction mixture and stirring is continued for another 30 minutes. The reaction mixture was poured into water, the aqueous phase was extracted with ethyl acetate and the combined organic phases were washed with brine.

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After drying over sodium sulfate and concentration in vacuo, 2.44 g of crude product is obtained, which is chromatographed on alumina (neutral, ΠΙ activity level) to give 1.8 g of the title compound. IR (KBr): 2230 cm -1 (triple bond)

c) 17β-Hydroxy-17α- (prop-1-ynyl) -β1,19- (o-phenylene) 4-dodsten-3-one

By acidic cleavage similar to that described in Example le)

From 1.5 g of product obtained in step b), 738 mg of the title compound is obtained.

Example 3

$ 17-Hydroxy-17- (prop-l-ynyl) -]] $, 19- (p-phenylene), 46-androstadien-3-one

a) 77 g of product of β, 19- (o-Phenylene) -4-androstene-3,17-dione, obtained by the reaction sequence of Examples 1a), 1b) and 2a) in the same manner as in Example le) we cut it into a compound.

[a] D = + 116 ° (CHC1 _3, C = 0.51)

Mp 284-288 ° C

b) The product obtained in Step 19, 19- (o-Phenylene) -3-ethoxy-3,5-andostadiene-17-one ga) is added to 85 ml of absolute dichloromethane in 25 ml of ethanol and 6.7 ml of ortho-formic acid triethyl ester, and At 0 ° C, 170 mg of p-toluenesulfonic acid (monohydrate) was added. After stirring overnight at ice bath temperature, excess sodium bicarbonate solution was added and the aqueous phase was extracted with dichloromethane. The combined organic phases are washed with saturated sodium chloride, dried over sodium sulfate and concentrated in vacuo. 11.3 g of crude product are obtained. After crystallization from a few drops of pyridine-containing ethanol, 5.43 g of the title crystalline product is isolated.

[α] D = + 39 ° (CHCl ₃ ; c = 0.5)

Mp 182-186 ° C.

c) From the compound obtained in step 17- (Prop-1-inyl) -11,19- (o-phenylene) -3-ethoxy-35-androstadiene-17 $ -ol gb), 5.4 g of crude product are obtained as described in Example 2b). of purity sufficient for further reaction. The crude product was crystallized from ethanol (400 mg) to give the title compound (268 mg).

[α] D = -91 ° (CHCl ₃ ; c = 0.5)

M.p. 203-207 ° C.

d) The crude product of 17- (Prop-1-ynyl) -1,7-hydroxy-11,19- (o-phenylene) 46-androstadien-3-one gc) is obtained in 50 ml of 80% aqueous dioxane and 10 ml of a 10% aqueous sodium acetate solution. To this suspension was added 1.6 g of 1,3-dibromo-5,5-dimethylhydantoin in portions at 0 ° C. Meanwhile, the steroid is slowly coming into solution. After a reaction time of 2 hours, the reaction mixture was poured into water and the aqueous phase was extracted with dichloromethane. The combined organic layers were washed with saturated sodium thiosulfate solution and water, dried over sodium sulfate and concentrated in vacuo. The impurity 17- (prop-1-ynyl) -17-3-hydroxy-11β, 19- (ofenylene) -6-bromo-4-androsten-3-one thus obtained is dissolved in 48 ml of absolute dimethylformamide, 2.4 g of lithium bromide and 1.65 g of lithium carbonate are added under a shielding gas and the mixture is stirred for one hour at 100 ° C. After cooling to room temperature, the reaction mixture was poured into water, the aqueous phase was neutralized with 4N hydrochloric acid, cooled in an ice bath and stirred at this temperature for one hour. The precipitated steroid is filtered by suction. 4.14 g of slightly impure crude product are obtained, which are of sufficient purity for the next reaction. Crystallization from 1.14 g of crude product from diisopropyl ether gives 638 mg of the title compound.

[a] D = +80 (CHC1 _3, C = 0.5). mp 215-217 ° C.

Example 4

17- (Prop-1-inyl-17 $ -hydroxy-1,9- (4-methoxy-o-phenylene) -4-androsten-3-one

a) 19- (2-Chloro-5-methoxyphenyl) -3,3-2,2-dimethyltrimethylenedioxy-9,11-androstene-5α-17-diol

Following the procedure of Example 1a), 15 g of 5a, 10aepoxy-3,3- (2,2-dimethyltrimethylenedioxy) -9 (11) -estrene-17-ol was reacted with 2-chloro-5-methoxybenzyl chloride.

15.5 g of the title compound are obtained.

b) 11 β, 19- (4-Methoxy-o-phenylene) -3,3- (2,2-dimethyl-trimethylenedioxy) -androstane-5α, 17-diol

Following the procedure of Example 1b), 15 g of the compound prepared in a) are obtained in the form of a white foam, 11.6 g.

[α] D = + 21.1 ° (CHCl ₃ ; c = 0.52) Mp 223-224 ° C (diisopropyl ether)

The title compound of step b) may also be prepared by the following synthesis:

a) 19- (2-Bromo-5-methoxyphenyl) -3,3- (2,2-dimethyltrimethylenedioxy) -911-androstene-5α-17-diol

150 g of 2-bromo-5-methoxybenzyl bromide are suspended in 1 liter of absolute diethyl ether under inert gas and 13.3 g of magnesium turnings are added. After the start of the Grignard reaction, the reaction temperature is kept below 30 ° C by cooling. After the formation of the Grignard reagent was completed, 50 g of 5a, 10a-epoxy-3,3- (2,2-dimethyltrimethylenedioxy) 9 (11) 08-τττη-5α, 17β-όϊO1 were added to 330 ml of absolute tetrahydrofuran with stirring. The reaction mixture is stirred for 1.5 hours and then worked up as described in Example 1a). After chromatography, 66.5 g of the title compound is isolated as a white foam.

128-130 ° C (diisopropyl ether / hexane).

β) 11 β, 19- (4-Methoxy-o-phenylene) -3,3- (2,2-dimethyl-trimethylenedioxy) -androstane-5α, 17-diol

As in Example 1b, 66 g of 19- (2-bromo-5-methoxyphenyl) -3,3- (2,2-dimethyltrimethylenedioxy) -9 (II) -androstene-5α, 4-diol. In 1.7 liters of absolute toluene, 34 ml of tributyltin hydride were reacted in the presence of 660 mg of 2,2-azoisobutyric acid nitrile in the presence of a radical. After completion of the reaction, the solvent was evaporated in vacuo and the residue was crystallized from diisopropyl ether. 49 g of the title compound are obtained in crystalline form.

c) 11 β, 19- (4-Methoxy-o-phenylene) -5a-hydroxy-3,3 (2,2-dimethyltrimethylene dioxy) androstan-17-one

Similar to Example 2a, 11 g was obtained in Step b)

The title compound was converted to the corresponding keto compound to give 9.53 g of the title compound as a white foam.

[α] D = + 33 ° (CHCl ₃ ; c = 0.55)

Mp 235-238 ° C

d) 17- (Prop-1-ynyl) -119,9- (4-methoxy-o-phenylene) -3,3- (2,2-dimethyl-trimethylenedioxy) -androstane-5-c, 17β-diol

By analogy to Example 2b, 4 g of the compound prepared in step c) are converted to the corresponding 17a-propynyl compound. After chromatography, 3.3 g of the title compound is isolated as a white foam.

IR (KBr): 2230 cm -1 (triple bond)

e) 17- (Prop-1-inyl) -1,7β-Ιήάη) χί-Ι1β, 19- (4-> ηείοχίo-phenylene) -4-androsten-3-one

Similarly to step le, 3 g of the compound prepared in step d) are converted to the corresponding 4-ene keto compound. 1.5 g of the title compound are isolated as a white foam.

[a] D = + 18 ° (CHC1 _3, C = 0.465).

Example 5

17- (3-ΗίάΓοχί ρΓορ-1 (Ζ) -βηίΙ] -) 7β-ΙιίάΓοχί-] 1β, 19 (4-methoxy-phenyl) -4-androsten-3-one

a) 17- [3- (Tetrahydropyran-2-yloxy) -prop-1-ynyl] -11β, 19- (4-methoxy-o-phenylene) -3,3- (2,2-dimethyl-trimethylene) -dioxy) -androstane-5a, 17β-όΐο1

To a solution of 5.7 g of 3- (tetrahydropyran-2-yloxy) -prop-1-ye in 100 ml of absolute tetrahydrofuran is slowly added dropwise 28.0 ml of a 15% solution of n-butyllithium in hexane at 0 ° C. -you. After stirring for 15 minutes at 0 ° C, a solution of 4 g of the product of Example 4c in 60 ml of absolute tetrahydrofuran is added dropwise at 0 to + 5 ° C. The mixture was stirred at room temperature for 3 hours, then poured into ice water and extracted with ethyl acetate. The organic phase is dried over sodium sulfate, concentrated in vacuo and the crude product is chromatographed on alumina (neutral, activity III). 4.36 g of the title compound is isolated as a white foam. M.p. 150-153 ° C (diisopropyl ether) [1: 1 mixture of tetrahydropyranyl ethers]

b) 17- [3- (Tetrahydropyran-2-yloxy) -prop-1 (Z) -enyl] -β, 19- (4-methoxy-o-phenylene) -3,3- (2,2-dimethyl-trimethylenedioxy) ) -androstane-5 (b.p. 17β-άΐοΙ ga) To a solution of the product prepared in step (17β-άΐοΙ ga) in tetrahydrofuran (75 mL) was added pyridine (5 mL) and palladium on barium sulfate (400 mg, 10% palladium) and hydrogenation at room temperature and pressure. After hydrogen uptake ceased, the catalyst was removed by filtration and the filtrate was evaporated. 3.91 g of the title compound are obtained in the form of a yellow foam.

c) 17- [3-Ηίάι · οχί-ρΓορ-1 (Ζ) -εηίΙ] -] 7β-Ιιίάη) χί11β, 19- (4-Methoxy-o-phenylene) -4-androsten-3-one

3.5 g of the compound obtained in step b) were cleaved as described in Example le). 1.5 g of the title compound are obtained in the form of a white foam.

[a] D = + 60 ° (CHC1 _3, C = 0.5)

Example 6

17- (Cyanomethyl) -17β-hydroxy-11β, 19- (4-methoxyphenylene) androsten-3-one

a) 11β, 19-4- (Methoxy-o-phenylene) -3,3- (2,2-dimethyl-trimethylenedioxy) -androstane- [17 (β-1J-spiro3 '] -oxiran-5a-ol

Under a shielding gas, 1 g of ketone prepared in step 4c) is dissolved in 20 ml of absolute dimethylformamide and 2.04 g of trimethylsulfonium iodide and 1.40 g of potassium tert-butylate are added at 0 ° C. The reaction mixture was slowly warmed to room temperature overnight with stirring, then poured into saturated ammonium chloride solution and the aqueous layer was extracted several times with ethyl acetate. The combined organic phases were dried over sodium sulfate, concentrated in vacuo and the residue chromatographed on alumina (neutral, activity III). 895 mg of the title compound is isolated as a white foam.

b) 17- (Cyanomethyl) -11β, 19- (4-methoxy-o-phenylene) 3,3- (2,2-άίηιείίΙ-ΐηηιείίΙόη-άίοχί) -αηάη) $ ζΐάη-5α, 17βdiol

Under a shielding gas, 850 mg of epoxide prepared in step a) is dissolved in 17 ml of absolute ethanol and a solution of 1.7 g of potassium cyanide in 3.4 ml of water is added. The reaction mixture was then heated at 50 ° C overnight, poured into ice water and extracted several times with ethyl acetate. The combined organic layers were dried over sodium sulfate and evaporated to dryness in vacuo. The residue was chromatographed on alumina (neutral, ΙΠ activity level). 815 mg of the title compound is isolated.

IR (KBr): 2250 cm <-1> (C = N triple bond).

c) 17- (ααηο-ηιβίίΙ) -17β-ΙιίάΓοχί-11β, 19- (4-ηιείοχΐo-phenylene) -4-androsten-3-one

800 mg of the compound prepared in step b) were converted to the corresponding 4-ene-3-keto compound as described in Example le). 575 mg of the title compound are obtained.

[.alpha.] D @ 20 = 59 DEG (CHCl3; 0.505) m.p. 155-156 DEG C. (ethyl acetate / hexane).

Example 7

17- (Prop-1-inyl) -17β-hydroxy-11β, 19- (4-methoxyphenylene) -4,6-androstadiene-3-one

a) 1- [4- (Methoxy-o-phenylene) -4-androstene-317dione

Similarly to Example le, 11.2 g of the material prepared in Example 4c) are converted to the corresponding 4-ene-3-keto compound. 7.6 g of the title compound are isolated.

[α] D = 130 ° (CHCl ₃ , c = 0.5)

184-187 ° C (ethyl acetate)

b) 1- [19- (4-Methoxy-o-phenylene) -3-ethoxy-3,5-androstadiene-17-one

As in Example 3b, 5 g of the product prepared in step a) are reacted with ethanol. 2.45 g of crystalline title compound are obtained.

[α] D = 57 ° (CHCl ₃ ; c = 0.5)

174-176 ° C

c) 17- (Prop-1-ynyl) -ltf, 19- (4-methoxy-o-phenylene) -3-ethoxy-35-androstadiene-17β-οΙ

Similar to Example 3c, 2.4 g was prepared in b)

HU 210 532 A9 is reacted with a keto compound. 2.45 g of crude product are isolated.

[α] D = -86 ° (CHCl ₃ ; c = 0.505)

M.p. 168-171 ° C (ethanol)

d) 17- (Prop-1-ynyl) -17β-hydroxy-11β, 19- (4-methoxyphenylene) -4,6-androstadiene-3-one

As in Example 3d, the crude product of 2.35 gc) is converted to the corresponding 4,6-diene-3-keto compound. The crude product was chromatographed on silica gel to give 1.43 g of the title compound. [a] = § 132 '(CHC1 _3, C = 0.5)

M.p. 237-242 ° C (ethyl acetate)

Example 8

17- (3-Hydroxyprop -] (Z) -enyl) -1,7 ° -hydroxy-11,19 [4- (methylthio) -o-phenylene] -4-androsten-3-one

a) 19- [2-Chloro-5- (methylthio) phenyl] -3,3- (2,2-dimethyltrimethylenedioxy) androstene-5α, 17β-diol

As in Example 1a), 34 g of 5a, 10a-epoxy-3,3 (2,2-dimethyltrimethylenedioxy) -9 (11) -androstene-17-ol

94.5 g of 2-chloro-5- (methylthio) benzyl chloride are reacted. Chromatography afforded 43.2 g of the title compound as a white foam.

b) The material obtained in step 11-19- [4- (Methylthio) -o-phenylene] -3,3- (2,2-dimethyl-5a-17-diol) ga) is dissolved in 750 ml of absolute tetrahydrofuran and solution at -78 ° C was added dropwise to a mixture of 3.79 g of lithium and 3.4 liters of liquid ammonia. After stirring for 45 minutes, a mixture of methanol (200 ml), tetrahydrofuran (200 ml) and methyl iodide (4.6 ml) was added slowly at the same temperature. After the addition is complete, the precipitated material is processed as described in Example 1 (b). 18.37 g of pure product crystallized directly from the crude product.

M.p. 173-176 ° C (ethyl acetate).

c) 11,19,19- [4- (Methylthio) -o-phenylene] -5a-hydroxy-3,3 (2,2-dimethyl-trimethylenedioxy) -andman-17-one

Similarly to Example 13c, 18 g of the material prepared in b) are converted to the corresponding 17-keto compound with 21.47 g of aluminum triisopropylate and 156 ml of cyclohexanone in 780 ml of absolute toluene. Chromatography on alumina (neutral, ΠΙ activity level) afforded 13.98 g of the title compound as a white foam.

[α] D = 41.8 ° (CHCl ₃ ; c = 0.5)

224-225 ° C (ethyl acetate / hexane)

d) 17- [3- (Tetrahydropyran-2-yloxy) -prop-1-ynyl] -p, 19- [4- (methylthio) -o-phenylene] -3,3- (2,2-dimethyl- trimethylenedioxy) androstane-5a, 173-diol

Similarly to Example 5a, 13.8 g of the product prepared in step c) are reacted with 19 g of 3- (tetrahydropyran-2-yloxy) -prop1-yn. Chromatography gave 15.65 g of the title compound as a white foam.

IR (KBr): 2230 cm ^-1 (triple bond)

e) 17- [3- (Tetrahydropyran-2-yloxy) -prop-1 (Z) -enyl] -11β, 19- [4- (methylthio) -o-phenylene] -3,3- ( 2,2-Dimethyl-trimethylenedioxy] -androstane-5α, 17β-diol

Similarly to Example 5b, 15.5 g of the product prepared in step d) are hydrogenated in the presence of hydrogen, palladium catalyst poisoned with 1.51 g of 10% barium sulfate and 18.9 ml of pyridine. Chromatography gave 14.15 g of the title compound as a white foam.

f) 17- (3-Hydroxy-prop-1 (Z) -enyl) -17H-hydroxyl-1,9- [4- (methylthio) -o-phenylene] -4-androsten-3-one

5.5 g of the olefin obtained in step e) is converted to 4-ene-3-keto compound in 200 ml of acetone with 5 ml of 4N aqueous hydrochloric acid. Chromatography on silica gel gave 2.34 g of the title compound as a white foam.

[α] D = 86 ° (CHCl ₃ ; c = 0.51)

146-148 ° C (ethyl acetate / hexane)

Example 9

17- (3-Hydroxy-prop-l (Z) -enyl) -5- (X, 17-dihydroxy]] $, 19- [4- (methylthio) -o-phenylene] -androstan-3-one

a) 17- (3-Hydroxy-prop-1 (Z) -enyl) -5c, 17? -dihydroxyl-, 19- [4- (methylthio) -o-phenylene] -androstan-3-one g 8e. ) was converted to the desired 3-keto compound in 50 ml of 70% acetic acid at room temperature.

The reaction mixture was then diluted with water and the aqueous layer was extracted with dichloromethane. The combined organic layers were washed successively with saturated sodium hydrogen sulfate solution and saturated sodium chloride solution and then dried over sodium sulfate. The solvent was removed in vacuo and the residue was chromatographed on silica gel. 2.66 g of the title compound are obtained in the form of a white foam. [a] D = 5 '(CHC1 _3, C = 0.5)

193-195 ° C

Example 10

17- (3-Hydroxy-prop-l (Z) -enyl) -17-hydroxy- $] $ l, 19 [4- (methylsulfinyl) -o-phenylene] -4-androsten-3-one

a) 17- [3- (Tetrahydropyran-2-yloxy) -prop-1 (Z) -enyl] -11,19- [4- (methylsulfenyl) -o-phenylene] -3,3- ( 2,2-Dimethyltrimethylenedioxy) androstane-5-t, 17-diol ga Example 8e) was dissolved in a mixture of 45 ml of tetrahydrofuran, 45 ml of methanol and 10 ml of water and 5.1 g of sodium periodate was added. After stirring at room temperature overnight, the reaction mixture was filtered through celite, and the filtrate was diluted with ethyl acetate. The organic layer was washed with saturated sodium hydrogen sulfate solution, dried over sodium sulfate and concentrated in vacuo. The residue was chromatographed on alumina (neutral, degree of activity ivit). 3.94 g of the title compound are isolated in the form of a white foam.

b) 17- (3-Hydroxy-prop-1 (Z) -enyl) -17β-hydroxy-11β, 19- [4- (methylsulfinyl) -o-phenylene] -androsten-3-one

Similarly to Example le, 3.8 g of the material prepared in step a) is converted to the 4-ene-3-keto compound. After chromatography on silica gel, 1.66 g of the title compound is isolated.

[α] D = 5Γ (CHCl ₃ ; c = 0.5).. example

17- (3-Hydroxyprop-1 (Z) -enyl) -17 S -hydroxy-11β, 194-methylsulfinyl-o-phenylene-androsten-3-one

a) 17- (3-Hydroxyprop-1 (Z) -enyl) -17 S-hydroxymethyl-β, 19- [4- (methylsulfinyl) -o-phenylene] -dandhen-3-one

Similar to Example le, 2.5 g of Example 8d) was prepared14

Adjusted substance A9 is cleaved to the corresponding 4-ene-3-keto compound. The product was chromatographed on silica gel to give 1.13 g of the title compound as a white foam.

Example 72

17- (3-Hydroxy-prop-l (Z) -enyl) -17-hydroxy-$ ll $, 19 [4- (ethylthio) -o-phenylene] -androstene-3-oti

a) 7β, 19- [4- (Ethylthio) -o-phenylene] -3,3- (2,2-dimethyltrimethylenedioxy) androstane-5α, 17β-diol

Similarly to Example 8b, 10 g of the material prepared in Example 8a are treated with 620 mg of lithium and replaced with methyl iodide.

14.7 ml of ethyl iodide are reacted. The crude product was combined with ethyl acetate / hexane to give 4.62 g of the title compound as a crystalline product.

[α] D = 39 ° (CHCl ₃ ; c = 0.5)

Mp 164 ° C

b) Section 11, 19- [4- (Ethylthio) -o-phenylene] -5a-hydroxy-3,3 (2,2-dimethyl-trimethylenedioxy) -androstan-17-one

As in Example 13c, 4.5 g of the material prepared in step a) is converted to the corresponding 17-keto compound. After chromatography, 3.4 g of the title compound are isolated.

[α] D = 44 ° (CHCl ₃ ; c = 0.505)

IR (KBr): 1740 cm @ -1 (five membered ring lactone).

c) 17- [3- (Tetrahydropyran-2-yloxy) -prop-1-ynyl] -11,19- [4- (ethylthio) -o-phenylene] -3,3- (2,2) -dimethyl-trimethylenedioxy) -androstane-5a, $ 17-diol

Similarly to Example 5a, 3.2 g of 3- (tetrahydropyran-2-yloxy) -prop-1-yne were reacted with 3.2 g of the ketone prepared in b). After chromatography, 3.25 g of the title compound is isolated as a white foam.

IR (KBr): 2230 cm -1 (triple bond)

d) 17- [3- (Tetrahydropyran-2-yloxy) -prop-1 (Z) -enyl] -7,7,7- [4- (ethylthio) -o-phenylene] -3,3 - (2,2-dimethyltrimethylenedioxy) androstane-5α, 17β-diol

As in Example 5b, 3.1 g of the product of step c) are hydrogenated in the presence of 300 mg of 10% palladium on carbon poisoned with 3.75 ml of pyridine. After chromatography, 2.85 g of the title compound is isolated as a white foam.

e) 17- (3-Hydroxyprop-1 (Z) -enyl) -17 S -hydroxy-77β, 19- [4- (ethylthio) -o-phenylene] -androsten-3-one

2.7 g of the olefin obtained in step d) is converted to the corresponding 4-ene-3-keto compound with 2.5 ml of 4N aqueous hydrochloric acid in 100 ml of acetone. After chromatography on silica gel, 1.35 g of the title compound is isolated as a yellowish foam. [α] D = 85 ° (CHCl ₃ ; c = 0.5)

Example 13

17- (Prop-1-imyl) -17 S -hydroxy-11 S, 19- [4- (dimethylamino) -o-phenylene] -andm-sten-3-one

a) 19- [2-Chloro-5- (dimethylamino) phenyl] -3,3- (2,2-dimethyltrimethylenedioxy) -9 (11) -androstene-5a, 17? -diol

As in Example 1a), 15 g of 5a, 10a-epoxy-3,3 (2,2-dimethyltrimethylenedioxy) -9 (11) -estrene-17β-ol are 2-chloro-5- (dimethylamino). 14.39 g of the above compound are obtained with benzyl chloride.

b) 11β, 19- [4- (Dimethylamino) -o-phenylene] -3,3- (2,2-dimethyl-trimethylene-dioxy) -androstane-5a, 17β-οίο1

Similarly to Example 1b, 14 g of the compound prepared in a) are obtained in the form of a white foam, 9.9 g.

c) 11,19- [4- (Dimethylamino) -o-phenylene] -5a-hydroxy-3,3- (2,2-dimethyl-trimethylene-dioxy) -androstan-17-one

11.5 g of the compound obtained in b) are dissolved in 500 ml of toluene and 13.8 g of aluminum isopropylate and 100 ml of cyclohexanone are successively added. The reaction mixture is then refluxed and the solvent is stirred for ca. one third of it is distilled off. After cooling, the mixture was poured into ice water, the resulting emulsion was filtered through celite, the filtrate was washed thoroughly with ethyl acetate, the organic phase was separated from the filtrate, dried over sodium sulfate and concentrated in vacuo. The residue was chromatographed on alumina (neutral, activity III) to give 8.13 g of the title compound.

Recrystallization of 130 mg of this compound in ethyl acetate gave 67 mg of crystalline 1- [19- [4- (dimethylamino) -phenylene] -5a-hydroxy-3,3- (2,2-dimethyltrimethylenedioxy). -androstan-17-one.

[a] _D = 28 ° (CHC1 _3, C = 0.5)

264-267 ° C

d) 17- (Prop-1-ynyl) -11,19- [4- (dimethylamino) -phenylene] -3,3- (2,2-dimethyl-trimethylenedioxy) -androstane- diol

As in Example 2b, 3 g of the compound obtained in step c) are converted to the corresponding 17a-propynyl compound. After chromatography, 2.6 g of the title compound is isolated as a yellowish foam.

IR (KBr): 2235 cm ^-1 (triple bond)

e) 17- (Prop-1-ynyl) -17 S -hydroxy-11 S, 19- [4- (dimethylamino) -o-phenylene] -andmmen-3-one

Similarly to Example le, 2.5 g of the product of step d) is converted to the corresponding 4-ene-3-keto compound. 1.58 g of the title compound is isolated as a white foam.

[α] D = + 28 ° (CHCl ₃ , c = 0.51)

M.p. 231-234 ° C (ethyl acetate)

The 2-chloro-5- (dimethylamino) -benzyl chloride required for Step 13a is prepared as follows:

a) 2-Chloro-5-aminobutzyl alcohol

Under a shielding gas, 300 g of lithium aluminum hydride is weighed at 0 ° C in 3 L of tetrahydrofuran and 500 g of 5-amino-2-chlorobenzoic acid (85%, technical grade) are added in portions. The reaction mixture was then slowly warmed to room temperature and stirred at this temperature overnight. After working up, the reaction mixture is cooled to 0 ° C and the excess lithium aluminum hydride is carefully quenched with saturated ammonium chloride solution. The organic phase is then separated from the precipitated material and the pellet is washed several times with ethyl acetate and dichloromethane. The combined organic phases are washed neutral with saturated sodium chloride solution, dried over sodium sulfate and concentrated in vacuo. 242 g of crude 2-chloro-5-aminobenzyl alcohol are obtained, the purity of which is sufficient for the following reaction. 1 H-NMR (CDCl ₃ ) [δ]: 6.3-7.15 (3H, m, aromatic protons; 4.55 (2H, s, benzyl protons).

HU 210 532 A9

β) 2-Chloro-5- (dimethylamino) -benzyl alcohol

51.8 g of sodium borohydride are suspended in a mixture of 30 g of 2-chloro-5-aminobenzyl alcohol and 1 liter of tetrahydrofuran, and the suspension is added dropwise with cooling and stirring to 235 ml of 2M sulfuric acid and 88 ml of 38% formalin solution. at a temperature of -10 to 20 ° C. After the addition was complete, the reaction mixture was made strongly basic with solid sodium hydroxide and diluted with water. The organic phase is separated off, the aqueous phase is extracted several times with dichloromethane and the combined organic phases are washed neutral with saturated sodium chloride solution. It was then dried over sodium sulfate and concentrated in vacuo. 24 g of 2-chloro-5- (dimethylamino) -benzyl alcohol are obtained in the form of an oil, 1 H-NMR (CDCl ₃ ) [δ]: 6.4-7.25 (3H, m, aromatic protons); 4.67 (3H, s, benzyl protons); 2.92 (6H, s, protons of the two methyl groups).

γ) 2-Chloro-5- (dimethylamino) -benzyl chloride

23.8 g of N-chlorosuccinimide are added to 600 ml of absolute methylene chloride, the mixture is cooled to 0 ° C and 15.6 ml of dimethylsulfide is added slowly. The resulting slurry was then cooled to -39 ° C and 20 g of 2-chloro-5- (dimethylamino) benzyl alcohol was carefully added. The mixture was then heated to 0 ° C and stirred at this temperature for 3 hours, then diluted with methylene chloride and poured into ice water. The organic layer was separated, washed with brine, dried over sodium sulfate and concentrated in vacuo. The residue was chromatographed on alumina (neutral activity ΠΙ) with hexane. 17.2 g of 2-chloro-5- (dimethylamino) -benzyl chloride are obtained. 1 H-NMR (CDCl ₃ ) [δ]: 6.4-7.3 (3H, m, aromatic protons); 4.61 (2H, s, benzylic protons); 2.92 (6H, s, protons of the two methyl groups).

Example 14

17β-Hydroxy-17α-methoxymethyl-11β, 19- [4- (dimethylamino) -phenylene] -4-androsten-3-one

a) 11,19- [4- (Dimethylamino) -o-phenylene] -3,3- (2,2-dimethyl-trimethylene-dioxy) -androstane- [17β-1,1'] -spim-3-oxirane- 5a-ol

2.5 g of the compound of Example 13c) are dissolved in 50 ml of absolute dimethylformamide under a shielding gas, and the solution is cooled to 0 [deg.] C. and 5 g of trimethylsulfonium iodide and 3.4 g of potassium tert-butylate are added successively. added. The mixture was stirred until the reaction was complete (TLC control). The reaction mixture was poured into ice water, the aqueous phase was extracted with ethyl acetate, the organic phase was washed with brine and dried over sodium sulfate. The solvents were removed and the residue was chromatographed on alumina (neutral, activity III). 2.1 g of the title compound are isolated as a white foam.

b) 17- (Methoxymethyl) -! 7 β-, 19- [4- (dimethylamino) -phenylene-3,3- (2,2-dimethyl-trimethylenedioxy) -androstane-5α, 7β-άίοΙ ga) was prepared in 40 ml of 3M methanolic sodium methylate. solution, and then the solution is heated under reflux under reflux. After cooling, the reaction mixture is poured into water, the aqueous phase is extracted with dichloromethane and the organic phase is washed with brine. The organic layer was dried over sodium sulfate, concentrated in vacuo and the residue chromatographed on alumina (neutral, activity III). 1.41 g of the title compound is isolated in the form of a white foam.

c) 7,7-hydroxy-17- (methoxymethyl) -17β, 7,9-4-dimethylamino-o-phenylene-4-androsten-3-one

Similarly to Example le, 1.3 g of the product of step b) is converted to the corresponding 4-ene-3-keto compound. 0.75 g of the title compound is obtained in the form of a white foam.

[a] D = * (CHC1 _3, C = 0.5)

124-127 ° C

Example 75

17- (Cyanomethyl) -17β-hydroxy-77β, 7β- [4- (dimethylamino) -phenylene] -androsten-3-one

a) 17- (Cyanomethyl) -11,19-4-dimethylamino-o-phenylene-3,3- (2,2-dimethyltrimethylenedioxy) androstane5α, 17β-άϊοΙ

Similar to Example 6b, 2.2 g of the epoxide prepared in Example 14a) are treated with 4.22 g of potassium cyanide in 8.4 ml of water and 42 ml of ethanol. After chromatography 1.95 g of the title compound is isolated. IR (KBr): 2245 cm @ -1 (C3-N3 triple bond).

b) 17- (Cyanomethyl) -17H-hydroxy-11,19- [4- (dimethylamino) -phenylene] -androsten-3-one

1.9 g of the cyanide prepared in step a) are converted to the corresponding 4-ene-3-keto compound as in example le). 1.23 g of the crude product is crystallized directly from the crude product. Chromatography of the mother liquor afforded an additional 138 mg of the desired cyano compound.

[a] _D = 77 ° (CHC1 _3, C = 0.5)

172-176 ° C

Example 76

17- (3-Hydroxy-prop-l-ynyl) -17fi-hydroxy-ll $, 19- [4- (dimethylamino) -o-phenylene] androsten-3-one

a) 17- (3-Hydroxyprop-1-ynyl) -11β, 19- [4- (dimethylamino) -ophenylene] -3,3- (2,2-dimethyltrimethylenedioxy) androstane- 5a, 17β-όΐο1

As in Example 5a, 10 g of the keto compound of Example 13c) are reacted with 55.3 g of 3- (tetrahydropyran-2-yloxy) -propine and 247 ml of 15% n-butyllithium in hexane. Chromatography gave 11.74 g of the title compound as a white foam. IR (KBr): 2230 cm ^-1 (triple bond)

b) 17- (3-Hydroxyprop-1-ynyl) -7β-hydroxy-11β, 19 [4- (dimethylamino) -o-phenylene] -androsten-3-one

Similarly to Example le, 11.74 g of the compound prepared in a) are converted to 6.97 g of the title compound.

[a] D = 25.6 "(CHC1 _3, C = 0.5)

M.p. 251-253 ° C (ethyl acetate)

HU 210 532 A9

Example 17

17- (3-Hydroxyprop-1 (Z) -enyl) -17 S -hydroxy-11,19 [4- (dimethylaminophophenylene) androsten-3-one

a) 17- (3-Hydroxyprop-1 (Z) -enyl) -1,7 H -hydroxyl-, 19- [4- (dimethylamino) -ophenylene] androsten-3-one

As in Example 5b, 6.5 g of the acetylene compound of Example 16b) were converted to the corresponding Z-olefin. After chromatography on silica gel, 4.76 g of the title compound is isolated in the form of a white foam.

[α] D = 71 ° (CHCl ₃ ; c = 0.5)

Example 18

I7 $ $ ll-hydroxy-19- (4-hydroxy-o-phenylene) -4-androsten-3-one

a) A methoxy compound prepared in a similar manner to Example 1p, 19- (4-Hydroxy-o-phenylene) -3,3- (2,2-dimethyltrimethylenedioxy) androstane-5a, 17β-diol g 4β) in 500 ml of absolute dimethyl formamide, and 28.2 g of sodium methane thiolate are added under a protective gas. Under an inert gas atmosphere, the reaction mixture was refluxed for 3 hours, cooled to room temperature and poured into ice water (8 L). The mixture is stirred at room temperature until the crude product precipitates as a solid. This material is filtered off with suction, washed with water and dried in vacuo. 49.2 g of the crude title compound are obtained in the form of a white solid which is of sufficient quality for further reaction.

[α] § = 2Γ (CHC1 _3, C = 0.5)

267-270 ° C (ethyl acetate)

b) The phenol prepared in step 17-hydroxy-11β, 19- (4-hydroxy-o-phenylene) -4-androsten-3-one ga) was prepared as in Example 1c) with 3 ml of 4N aqueous hydrochloric acid in 60 ml of acetone. Is converted to a -3-keto compound. 1.05 g of compound is isolated as a white foam.

M.p. 242-245 ° C (ethyl acetate)

Example 19

17β-Hydroxy-11β, 19-4- (trifluoromethylsulfonyloxy) o-phenylene] -4-dodsten-3-one

a) 17-Hydroxy-11,19- [4- (trifluoromethylsulfonyloxy) -o-phenylene] -4-androsten-3-one The phenol prepared in Example 18b) is dissolved in 250 ml of absolute dichloromethane, and the solution

17.3 g of 4- (dimethylamino) pyridine are added. The solution was cooled to -50 ° C under protective gas and a solution of trifluoromethanesulfonic anhydride (4.76 mL) in absolute methylene chloride (30 mL) was added dropwise. After stirring at -50 ° C for 15 minutes, the reaction mixture was poured into saturated sodium bicarbonate solution and the aqueous phase was extracted with dichloromethane. The combined organic phases were washed with brine, dried over sodium sulfate and concentrated in vacuo. The residue was chromatographed on silica gel to give 11.37 g of the title compound as a yellowish foam.

M.p. 204-205 ° C (diisopropyl ether).

Example 20

17β-Hydroxy-11,19- [4- (2-trimethylsilyl) ethynyl) -phenylene] -4-androsten-3-one

a) The triflate compound prepared in Example 19a) from $ 17-Hydroxy-11 $ 19-4-2-trimethylsilylethynyl-offenylene] -4-androsten-3-one is dissolved in 10 ml of absolute dimethylformamide and a protective gas is added. 1.18 ml of triethylamine, 1.39 ml of trimethylsilylacetylene and 49 mg of palladium tetrakis (triphenylphosphine) are added. The reaction mixture was then heated at 110 ° C for 1 hour, cooled to room temperature and diluted with ethyl acetate. The mixture was filtered through celite, the filtrate washed several times with saturated sodium chloride solution, the organic layer was separated, dried over sodium sulfate and concentrated in vacuo. The residue was chromatographed on silica gel to give 656 mg of the title compound as a white foam. 267271 ° C (diisopropyl ether)

Example 21

17- (Prop -] - inyl) -17 S -hydroxy -] - $, 19- [4- (2-trimethylsilylethynyl) -o-phenylene] -4-androsten-3-one

a) 17β, 7 9- [4- (Trifluoromethylsulfonyloxy) -o-phenylene] -3,3- (2,2-dimethyl-trimethylenedioxy) -androstane 5a, 17-diol g 18a) The phenol prepared in Example 1A was reacted with 14.93 ml of trifluoromethanesulfonic anhydride, as in Example 19a). After chromatography, 37.3 g of the title compound is isolated as a white foam.

b) with 11β, 19- [4- (2-Trimethylsilylethynyl) -o-phenylene J-3,3 (2,2-dimethyl-trimethylenedioxy) -distane-5a, 17? -diol) The compound prepared in Step 3a was treated with 17.3 mL of trimethylsilylacetylene in a similar manner to that described in Example 20a). After chromatography on alumina (neutral, activity level III), 11.7 g of the title compound are isolated in the form of a white foam.

IR (KBr): 2150 cm ^-1 (triple bond on the aromatic group)

c) 11,19,19- [4- (Trimethylsilylethynyl) -o-phenylene] -5-hydroxy-3,3- (2,2-dimethyl-trimethylene-dioxy) -distane17-one

11.2 g of the material prepared in step b) are oxidized, as in Example 2a), to 11.69 g of chromium trioxide to give the corresponding 17-keto compound. After chromatography on alumina (neutral, ΠΙ activity level), 9.05 g of the title compound is isolated in the form of a white foam.

[α] β = 5Γ (CHC1 _3, C = 0.5)

245-248 ° C (diisopropyl ether).

d) 17- (Pmp-1-ynyl) -11,19- (4- (2-trimethylsilylethynyl) -o-phenylene] -3,3- (2,2-dimethyl-trimethylene-dioxy) -androstane-5 a, $ 17-diol

The ketone prepared in Step Ige is reacted with propin as in Example 2b). After chromatography on alumina (neutral, ΠΙ activity level), 956 mg of the title compound is isolated in the form of a white foam.

IR (KBr): 2250 cm- ¹ (triple bond on the aromatic group)

2235 cm ^-1 (triple bond)

HU 210 532 A9

e) 17- (Prop-1-ynyl) -17 S -hydroxy-11 S, 19- [4- (2-trimethylsilylethynyl) -o-phenylene] -4-androsten-3-one

900 mg of the compound prepared in step d) are cleaved to the corresponding 4-ene-3-keto compound as in example le). After chromatography on silica gel, the title compound (471 mg) was isolated as a white foam.

[a] D = 59 ° (CHC1 _3, C = 0.505)

Example 22

17- (Prop-1-ynyl) -17 $ -hydroxy-11 $, 19- (4-ethynyl-o-phenylene) -androsten-3-one

a) 11,19- (4-Ethynyl-o-phenylene) -5a-hydroxy-3,3- (2,2-dimethyl-trimethylenedioxy) -androstan-17-one

1.5 g of the ketone prepared in Example 21c) are dissolved in 26 ml of absolute methanol and 1.1 g of anhydrous potassium carbonate are added. After stirring for 3 hours at room temperature, the reaction mixture was poured into saturated sodium chloride solution and the aqueous phase was extracted several times with dichloromethane. The combined organic phases were washed with brine, dried over sodium sulfate and concentrated in vacuo. The quality of the crude product (1.31 g) is sufficient for further reaction. Chromatography of the crude product (100 mg) on alumina (neutral, fok activity level) afforded 67 mg of the title compound as a white foam.

b) 17- (Prop-1-ynyl) -11,19- (4-ethynyl-o-phenylene) -3,3 (2,2-dimethyl-trimethylenedioxy) -androstane-5a, 17-diol

1.2 g of the product of step a) are reacted with propin in the same manner as in example 2b). After chromatography on alumina (neutral, activity III), 1.12 g of the title compound is isolated as a white foam.

IR (KBr): 2110 cm- ¹ (triple bond on the aromatic group)

2235 cm ^-1 (triple bond)

c) 17- (Prop-1-ynyl) -1,7 $ -hydroxy-11 $, 19- (4-ethynyl-offenylene) -androsten-3-one

The material prepared in step 1.1b) is converted to the corresponding 4-ene-3-keto compound as in step le). After chromatography on silica gel, 612 mg of the title compound is isolated as a white foam. [a] D = 41 * (CHC1 _3, C = 0.5)

Example 23

I7- (prop-l-ynyl) -17-hydroxy-ll $ $, 19- [4-2-trimethylsilylethyl) -o-phenylene] -4-androsten-3-one

a) $ 11,19- [4- (2-Trimethylsilylethyl) -o-phenylene] -5-hydroxy-3,3- (2,2-dimethyl-trimethylenedioxy) -androstan-17-one g Example 21c) The ketone prepared according to Example 1 is dissolved in 10 ml of absolute ethanol and hydrogenated under normal pressure in the presence of 10% palladium on carbon. After uptake of 2 equivalents of hydrogen, the reaction mixture was filtered through celite, the filtrate was washed with ethyl acetate, and the filtrate was concentrated in vacuo. The residue was chromatographed on alumina (neutral, activity III) to isolate 884 mg of the title compound.

b) 17- (Prop-1-ynyl) -11,19- [4- (2-trimethylsilylethyl) o-phenylene] -3,3- (2,2-dimethyltrimethylenedioxy) androstane -5ct, $ 17 -diol

850 mg of the ketone prepared in step a) are reacted with propin in the same manner as in Example 2b. After chromatography on alumina (neutral, fok activity level), 845 mg of the above compound is isolated in the form of a white foam.

IR (K Br): 2235 cm ^-1 (triple bond)

c) 17- (Prop-1-ynyl) -17β-hydroxy-11,19- [4- (2-trimethylsilylethyl) -o-phenylene] -4-androsten-3-one

800 mg of the compound prepared in step b) are converted to the corresponding 4-ene-3-keto compound as in step le). Chromatography on silica gel gave 512 mg of the title compound as a white foam.

[a] D = 23 "(CHC1 _3, C = 0.505)

Example 24

17- (Prop-1-inyl) -17β-hydroxy-11β, 19- (4-ethyl-o-phenylene) -4-androsten-3-one

a) 11,19- (4-Ethyl-o-phenylene) -5a-hydroxy-3,3- (2,2-dimethyl-trimethylenedioxy) -androstan-17-one g of the acetylene prepared in Example 22a). Compound III was hydrogenated as in Example 23a to give the corresponding ethyl compound. After chromatography on alumina (neutral, ΠΙ activity level), 3.63 g of the title compound is isolated in the form of a white foam.

b) 17- (Prop-1-ynyl) -11,19- (4-ethyl-o-phenylene) -3,3 (2,2-dimethyl-trimethylenedioxy) -androstane-5a, 17-diol

The compound prepared in step 1.5 (g) is reacted with propin in the same manner as in Example 2b. After chromatography on alumina (neutral, ΙΠ activity level), 1.43 g of the title compound is isolated as a white foam. IR (KBr): 2240 cm ^-1 (triple bond)

c) 17- (Prop-1-ynyl) -177-hydroxymethyl-11,19- (4-ethyl-o-phenylene) -4-androsten-3-one

The material prepared in step 1.3b) was converted to the corresponding 4-ene-3-keto compound as in Example le). After chromatography on silica gel, 879 mg of the title compound is isolated in the form of a white foam. [a] D = 18 '(CHC1 _3, C = 0.5)

M.p. 283-285 ° C (ethyl acetate)

Example 25

17- (3-Hydroxyprop-1 (Z) -enyl) -17 S -hydmxi-11,19 (4-ethylphenylene) -4-androsten-3-one

a) 17- [3- (Tetrahydropyran-2-yloxy) -pmp-1-ynyl] 11,19- (4-ethyl-o-phenylene) -3,3- (2,2-dimethyl-trimethylenedioxy) ) -andm-stan-5a, 17 $ -diol g The ethyl compound prepared in Example 24a) is reacted with 3- (tetrahydropyran-2-yloxy) prop-1-yl as described in Example 5a). After chromatography on alumina, 2.29 g of the title compound is isolated in the form of a white foam.

IR (KBr): 2240 cm ^-1 (triple bond)

b) 17- [3- (Tetrahydropyran-2-yloxy) -prop-1 (Z) -enyl]] - $, 19- (4-ethyl-o-phenylene) -3,3- (2,2) -dimethyl-dimethyltrimethylenedioxy) -androszlán-5, $ 17-diol

2.2 g of the acetylene compound prepared in step a) are:

HU 210 532 A9

As in Example 5b), it is hydrogenated to a Z-olefin. After chromatography on alumina (neutral, ΠΙ activity level), 1.95 g of the title compound is isolated in the form of a white foam.

c) 17- (3-Hydroxyprop-1 (Z) -enyl) -17 S -hydroxyl-1,9- (4-ethylphenylene) -4-dodsthen-3-one

The compound prepared in 1.9 gb) is cleaved to the corresponding 4-ene-3-keto compound as in example le). Chromatography on silica gel afforded 706 mg of the title compound as a white foam. [a] D = 62 '(CHC1 _3, C = 0.505)

127-129 ° C (ethyl acetate)

Example 26

17- (Prop-1-inyl) -17β-1ιίάη) -11β, 19- (4-vinyl-o-phenylene) -4-androsten-3-one

a) 11,19- (4-Hydroxy-o-phenylene) -50-hydroxy-3,3 (2,2-dimethyl-trimethylenedioxy) -androstan-17-one g prepared in Example 4c). - (4-Methoxy-o-phenylene) -5a-hydroxy-3,3- (2,2-dimethyl-trimethylenedioxy) androstan-17-one is converted to the corresponding phenol as in Example 18a). 16.8 g of crude product are obtained which are of sufficient purity for further reaction. The crude product (500 mg) was chromatographed on alumina for analysis to give the title compound (412 mg).

b) 11β, 19- [4- (Trifluoromethylsulfonyloxy) -o-phenylene] -5a-hydroxy-3,3- (2,2-dimethyl-trimethylenedioxy) -androstan-17-one

16.3 g of the phenol prepared in step a) are converted to the corresponding triflate as in Example 19a). Chromatography on silica gel gave 15.1 g of the title compound as a white foam.

IR (KBr); 1740 cm ' ¹ (5-membered ring ketone)

1215 and 1420 cm ¹ (triflate)

c) [beta], 19- (4-Vinyl-o-phenylene) -5a-hydroxy-3,3- (2,2-dimethyl-trimethylenedioxy) -androstan-17-one

1.5 g of the product obtained in step b) are dissolved in 18 ml of absolute dimethylformamide and 146 mg of palladium tetrakis (triphenylphosphine) and 207 mg of lithium chloride are added under a protective gas. After stirring for 5 min, 0.89 mL of tri (n-butyl) vinyl tin was added and the mixture was heated to 110 ° C. After 1 hour, the reaction mixture was cooled to room temperature, diluted with ethyl acetate and suction filtered through celite. The filtrate was washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate and concentrated in vacuo. The residue was chromatographed on alumina (neutral, activity III) to give 1.1 g of the title compound as a white foam.

d) 17- (Pmp-1-inyl) -11,19- (4-vinyl-o-phenylene) -3,3 (2,2-dimethyl-trimethylenedioxy) -androstane-5a, 17β-άϊοΙ gc The ketone prepared in step (a) is reacted with propin as in Example 2b). Chromatography on alumina (neutral, activity III) afforded 912 mg of the title compound as a white foam. IR (K Br); 2240 cm ^-1

e) 17- (Prop-1-ynyl) -17β-ΙιίάΓθχΐ-] 1β, 9- (4-νίηϊΙ-o-phenylene) -4-androsten-3-one

850 mg of the compound prepared in step d) are converted to the corresponding 4-ene-3-keto compound as in example le). After chromatography on silica gel, 485 mg of the title compound is isolated in the form of a white foam.

[a] D = 50 ° _(CHCl3; c = 0.505)

M.p. 243-245 ° C (diisopropyl ether)

Example 27

17- (Prop-1-inyl) -17β-hydroxy-11β, 19- (4- (2-propenyl) -o-phenylene] -4-androsten-3-one

a) f / β, 19- [4- (2-Propenyl) -o-phenylene] -5a-hydroxy-3,3- (2,2-dimethyl-trimethylenedioxy) -androstan-17-one

1.5 g of the material prepared in Example 26b are reacted with 0.36 ml of tetraallyl tin as in Example 26c. After chromatography on silica gel, 1.06 g of the title compound is isolated in the form of a white foam.

b) 17- (Prop-1-ynyl) -1H, 19- (4- (2-propenyl) -ophenylene] -3,3- (2,2-dimethyltrimethylenedioxy) androstane5α, 17β -άίοΙ

Similarly to Example 2b, the material obtained in Step Ig is reacted with propin. After chromatography on alumina (neutral, ΙΠ activity level), 942 mg of the title compound is isolated as a white foam.

IR (KBr): 2240 cm -1 (triple bond)

c) 17- (P rop-1-ynyl) -17β-hydroxy-11β, 19- [4- (2-ηη penyl) -o-phenylene] -androsten-3-one

900 mg of the material prepared in b) are converted to the corresponding 4-ene-3-keto compound as in example le). Chromatography on silica gel gave 397 mg of the title compound as a white foam.

[a] D = 18 '(CHC1 _3, C = 0.5)

275-277 ° C (dichloromethane)

Example 28

17β-ΗίάΓθχί-11β, 19- (4-acetyl-o-phenylene) -androsten-3-one

a) 11 triflate prepared according to Example 21a) from 11β, 9β- (4-Acetyl-o-phenylene) -3,3- (2,2-dimethyltrimethylenedioxy) androstane-5cn, 17β-άίοΙ g. Example 22a was reacted with 22.06 g of 1-ethoxyvinyl tributyltin. After chromatography on silica gel, 18.75 g of the title compound is isolated as a white foam. [a] D = 146 '(CHC1 _3, C = 0.5)

M.p. 179-1811 (diisopropyl ether)

b) The material obtained according to 17β-ηηοχϊ-11β, 19- (4-acetyl-o-phenylene) -androsten-3-one g) is converted to the corresponding 4-ene-3-keto compound as in example le). After chromatography on silica gel, 10.8 g of the title compound is isolated as a yellowish foam. 135-138 ° C (ethyl acetate / hexane)

Example 29

17- (Prop-1-ηηΐΙ) -17β-1ιϊάΓθχί-11β, 19- (4-acetyl-o-phenylene) -androsten-3-one

a) 11 β, 19- (4- (1,1- (2,2-Dimethyl-trimethylenedioxy) ethyl] -o-phenylene} -3,3- (2,2-dimethyl-trimethylenedioxy) - 5-androstene-17β-οΙ g of the product obtained in Example 28b) is 250 ml of absolute

Dissolve in toluene and add 25.7 g of 1,3-dimethylpropanediol and 1.86 g of pyridinium para-toluenesulfonate in succession. The reaction mixture is then refluxed for 4 hours and the resulting water is removed by azeotropic distillation. The reaction mixture was cooled to room temperature, poured into 5% ice-cold aqueous sodium hydroxide solution, and the aqueous layer was extracted with ethyl acetate. The combined organic phases were washed with brine, dried over sodium sulfate and concentrated in vacuo. The residue was chromatographed on alumina (neutral, ΠΙ activity level) to give 10.7 g of the title compound as a white foam.

b)? 1β, 19- {4- [1,1- (2,2-Dimethyl-trimethylenedioxy) ethyl] -o-phenylene] -3,3- (2,2-dimethyl-trimethylenedioxy) -5-androstene- 17-one

10.5 g of the product of step a) are converted to the corresponding 17-keto compound as in example 2a). 10.2 g of crude product are obtained which are of sufficient purity for further reaction. 500 mg of analytical material were chromatographed on alumina (neutral, ΙΠ activity level) and 443 mg of the title compound were isolated as a white foam.

[α] D = 43 ° (CHCl ₃ ; c = 0.5)

M.p. 244-246 ° C (ethyl acetate)

c) 17- (Prop-1-ynyl) -11β, 19- {4 - [], 1- (2,2-dimethyltrimethylenedioxy) ethyl] -o-phenylene} -3,3- ( 2,2-Dimethyl-trimethylene-dioxide) -5-androstene-17-β-οΙ

1.5 g of the crude product of step b) are reacted with propine in the same manner as in Example 2b). After chromatography on alumina (neutral, activity III), 1.35 g of the title compound is isolated as a white foam. IR (K Br): 2240 cm -1 (triple bond)

d) 17- (Prop-1-ynyl) -17 H -hydroxy-11 H, 19- (4-acetyl-offenylene) androsten-3-one

1.3 g of the material prepared in step c) are similarly cleaved to the corresponding 4-ene-3-keto compound as in example le). Chromatography on silica gel gave 747 mg of the title compound as a yellowish foam.

Mg = 36 '(CHCl ₃ ; c = 0.5)

186-187 ° C (ethyl acetate)

Example 30

I7- (Prop-2-ynyl) -I7 $ -hydroxy-lI $,] 9- (4-acetyl-o-phenylene) -4-androsten-3-one

a) 17- (3-Trimethylsilyl-prop-2-ynyl) -1,19,19- (4- (1,1 (2,2-dimethyl-trimethylenedioxy) ethyl] -o-phenylene} - 3.3 (2,2-dimethyl-trimethylene-dioxy) -5-androstene] 7 $ ol

1.5 g of the compound prepared in Step 29b are reacted with 2.3 ml of 1- (trimethylsilyl) prop-1-yl as in Example 5a). After chromatography on alumina (neutral, activity III), 1.31 g of the title compound is isolated in the form of a white foam. IR (K Br): 2170 cm-1 (triple bond)

b) 17- (Prop-2-ynyl) -1,7 $ -hydroxy-11,19- (4-acetyl-offenylene) -4-androsten-3-one

The material prepared in step 1.2 (g) is converted to the corresponding 4-ene-3-keto compound as in Example le). Chromatography on silica gel gave 547 mg of the title compound as a white foam. Mg = 91 '(CHCl ₃ ; c = 0.5)

M.p. 257-259 ° C

Example 31

17- (Prop-1-ynyl) -17 S -hydroxy-11 S, 19- (4-acetyl-o-phenylene) -4,15-addadien-3-one

a) 77 β, 19- (4- (1,1- (2,2-Dimethyl-trimethylenedioxy) ethyl] -o-phenylene} -3,3- (2,2-dimethyl-trimethylenedioxy) - 5,15 androstadiene-17β-οΙ

A solution of the compound prepared in Example 29b (1.89 g) in absolute tetrahydrofuran (20 mL) was added dropwise to a solution of lithium diisopropylamide (9.9 mmol) in absolute tetrahydrofuran (40 mL) at 0 ° C. Chlorotrimethylsilane (2.39 ml) was then added dropwise to the reaction mixture. After stirring for 30 minutes, the reaction solution is poured into ice-cold saturated sodium bicarbonate solution, the aqueous phase is extracted with ethyl acetate, and the organic phase is washed with water and saturated ammonium chloride solution, dried over sodium sulfate and the organic phase is evaporated in vacuo. 1.96 g of 17- (trimethylsilyloxy) 11,19- {4- [1,1- (2,2-dimethyltrimethylenedioxy) o-phenylene) 3,3- (2,2- dimethyltrimethylenedioxy-5,16-androstadiene is obtained in the form of a yellowish foam. This product is suspended in 23 ml of absolute acetonitrile and 1 g of palladium (II) acetate is added to the suspension. After stirring for 2 hours at room temperature, the reaction mixture was filtered through celite, the filtrate was washed with ethyl acetate, and the filtrate was concentrated in vacuo. The residue was chromatographed on alumina (neutral, ΙΠ activity level) and the title compound was isolated as a white foam (1.33 g).

IR (KBr): 1710 ^cm-1 (five-membered cyclic unsaturated ketone)

b) 17- (Prop-1-ηηϋ) -11β, 19- (4- (1,1- (2,2-Dimethyl-trimethylenedioxy) ethyl) -o-phenylene} -3,3- (2 , 2-dimethyl-trimethylene-dioxy) -5.15-diene-17.beta.-ol

1.3 g of the product prepared in step a) are reacted with propin in the same manner as in example 2b). After chromatography on alumina (neutral, activity III), 1.23 g of the title compound is isolated as a white foam.

IR (KBr): 2230 cm ^-1 (triple bond)

c) 17- (Prop-1-inyl) -17β-hydroxy-11β, 19- (4-acetyl-offenylene) -4,15-androstadiene-3-one

The material prepared in 1.1 gb) is cleaved to the corresponding 4-ene-3-keto compound as in Example le). After chromatography on silica gel, 617 mg of the title compound is isolated as a yellowish foam. Md = 114 '(CHC1 _3, C = 0.5)

189-191 ° C (ethyl acetate)

Example 32

17- (methoxymethyl) -17-hydroxy-$ $ ll, 19- (4-acetyl-ophenylene) -4-androsten-3-one

a) 11β, 19- (4- (1,1- (2,2-Dimethyl-trimethylenedioxy) ethyl] -o-phenylene} -3,3- (2,2-dimethyl-trimethylenedioxy) -5-androstene (17 (β-1 ') -spiro-3'] -oxirane g The compound prepared according to Example 29b) is prepared according to 14a).

Similarly to Example A9, 7.13 g of trimethylsulfonium iodide were reacted. Chromatography on alumina (neutral, activity III) afforded 3.76 g of the title compound as a white foam.

b) 17- (Methoxymethyl) -11β, 19- {4- [1,1- (2,2-dimethyltrimethylenedioxy [ethyl] o-phenylene) -3,3- (2,2-dimethyl) -trimethylenedioxy [5-androstene-17β-οΙ

1.8 g of the product prepared in step a) are reacted with sodium methylate as in example 14b. Chromatography on alumina (neutral, activity III) afforded 1.55 g of the title compound as a white foam.

c) 17- (Methoxymethyl- [17β-hydroxy-11β, 19- (4-acetylphenylene) -4-androsten-3-one)

1.5 g of the product obtained in step b) are cleaved to the corresponding 4-ene-3-keto compound as in example le). After chromatography on silica gel, 561 mg of the title compound is isolated as a yellowish foam.

[<X] D = 76 ° (CHC1 _3, C = 0.5)

Example 33

17- (Cyanomethyl [17 S] -hydroxy-11β, 19- (4-acetylphenylene [4-androsten-3-one)

a) 17- (Cyanomethyl [11β, 19- {4- [1,1- (2,2-dimethyltrimethylenedioxy] ethyl] -o-phenylene / -3,3- (2,2-dimethyltrimethylene) dioxo [5-androstene-17β-οΙ

1.8 g of the product obtained in Example 32a) are reacted with potassium cyanide as in Example 6b). After chromatography on alumina (neutral, activity III), 1.67 g of the title compound is isolated as a white foam.

IR (KBr): 2250 cm ^-1 (C = triple bond)

b) 17- (Cyanomethyl) -17β-hydroxy-11,19- (4-acetylphenylene [4-androsten-3-one)

The material from step 1.5 (g) is cleaved to the corresponding 4-ene-3-keto compound as in example le). Chromatography on silica gel gave 732 mg of the title compound as a white foam. [α] D = 83 ° (CHCl ₃ , c = 0.5)

184-185 ° C (dichloromethane)

Example 34

17- (Prop-1-ynyl) -17 H -hydroxy-11β, 19- (4-isopropenyl-o-phenylene) -4,15-androsten-3-one

a) 11β, 19- (4-Isopropenyl-o-phenylene) -3,3- (2,2-dimethyl-trimethylene-dioxy [D-stan-5a, 17? -diol)

Under a shielding gas, 1.94 sodium hydride in 20 ml of absolute dimethyl sulfoxide is heated until no further gas evolution occurs. The solution was then cooled to 0 ° C and methyl triphenylphosphonium bromide (61 mL) dissolved in absolute dimethyl sulfoxide was added dropwise. After stirring for 1 hour at room temperature, a solution of 10.3 g of the compound prepared in Example 28a) in 10 ml of absolute dimethyl sulfoxide is added dropwise and stirring is continued for a further 3 hours. The reaction mixture was poured into cold saturated sodium bicarbonate solution, the aqueous phase was extracted with ethyl acetate and the organic layer was washed with saturated sodium chloride solution. The combined organic phases were dried over sodium sulfate and concentrated in vacuo. The residue was chromatographed on alumina (neutral, ΠΙ activity level). 8.3 g of the title compound are thus obtained in the form of a white foam.

155-157 ° C (diisopropyl ether)

b) 11,19- (4-Isopropenyl-o-phenylene [5a-hydroxy-3,3 (2,2-dimethyl-trimethylenedioxy) -androstan-17-one)

8.1 g of the material prepared in step a) are oxidized with chromium trioxide in the same way as in step 2a). After chromatography on alumina (neutral, activity level III), 7.8 g of the title compound is isolated as a white foam.

M.p. 238-240 ° C (diisopropyl ether)

c) 17 - $ - (Prop-1-ynyl) -11,19- (4-isopropenyl-o-phenylene [hydroxy-3,3- (2,2-dimethyl-trimethylenedioxy) -androstane-5a] -7 $. diol

1.5 g of the product obtained in step b) are reacted with propin in the same manner as in example 2b). Chromatography on alumina (neutral, activity III) afforded 1.34 g of the title compound as a white foam.

IR (KBr): 2240 cm ^-1 (triple bond)

d) 17- (Prop-1-ynyl) -17b-hydroxy-11b, 19- (4-isopropenyl-o-phenylene) -4,15-androstadien-3-one

1.3 g of the compound obtained in step c) are converted to the 4-ene-3-keto compound as in example le). Chromatography on silica gel afforded 706 mg of the title compound as a white foam.

[a] = § 4Γ (CHC1 _3, C = 0.5)

M.p. 247-250 ° C (diisopropyl ether)

As a by-product, 354 mg of 17- (2-hydroxy-1β-hydroxy-11β, 19- [4- (1-methylhydroxyethyl) -o-phenylene] -4-androsten-3-one was isolated as a white foam. [α] D = 17 ° (CHCl ₃ ; c = 0.5)

222-224 ° C

Example 35

17- (Prop-1-inyl [17β-hydroxy-11β, 19- (4-isopropylphenylene [4.15-androstadiene-3-one)

a) 11,19- (4-Isopropyl-o-phenylene) -5a-hydroxy-3,3 (2,2-dimethyl-trimethylenedioxy [androstan-17-one g. However, hydrogenation is carried out in the presence of palladium catalyst until up to one equivalent of hydrogen is taken up. After chromatography on alumina (neutral, ΙΠ activity level), 1.83 g of the title compound is isolated in the form of a white foam.

b) 17- (Prop-1-inyl [11,19,19- (4-isopropyl-o-phenylene [

3,3- (2,2-dimethyltrimethylene-dioxy [androstan-5a, 17-diol $

1.8 g of the compound prepared in a) are reacted with propin in the same manner as in Example 2b). After chromatography on alumina (neutral, activity III), 1.81 g of the title compound is isolated in the form of a white foam.

c) 17- (Prop-1-ynyl) -17 H -hydroxy] - 1, 19- (4-isopropyl-o-phenylene [4,15-androstadien-3-one)

1.7 g of the compound prepared in step b) are cleaved to give 4-ene-3-keto compound as in example le). After chromatography on silica gel, 932 mg of the title compound is isolated as a white foam.

[α] D = 21 ° (CHCl ₃ ; c = 0.5)

240-243 ° C (ethyl acetate)

HU 210 532 A9

Example 36] 7- (3-Hydroxy-prop-1 (Z) -enyl) - 7 - (- hydroxy-11 H- (4-isopropenyl-o-phenylene) -4-androsten-3-one

a) 17- [3- (Tetrahydro-pyran-2-yloxy) -prop-1-ynyl] -11- (3,19- (4-isopropenyl-o-phenylene) -3,3- (2,2-dimethyl-) trimethylenedioxy-androstane-5a, 17 (3-diol g. Example 34b) is reacted with 3- (tetrahydropyran-2-yloxy) -prop-1-yl as in Example 5a). After chromatography on alumina (neutral, activity III), 2.1 g of the title compound is isolated in the form of a white foam.

b) 17- [3- (Tetrahydro-pyran-2-yloxy) -prop-1 (Z) -enyl] - 1- (3,19- (4-isopropenyl-o-phenylene) -3,3- (2, 2-Dimethyltrimethylene) The compound from step ga) is hydrogenated with Lindlar catalyst as in Example 5b). After chromatography on alumina (neutral, ΠΙ activity level), 1.78 g of the title compound is isolated in the form of a white foam.

c) 17- (3-Hydroxy-prop-1 (Z) -enyl) -17H-hydroxy-1,19- (4-isopropenyl-o-phenylene) -4-androsten-3-one

1.7 g of the compound obtained in step b) are cleaved to give 4-ene-3-keto compound as in example le). Chromatography on silica gel afforded 567 mg of the title compound as a white foam.

[a] D = 79 "(CHC1 _3, C = 0.5)

143-145 ° C (ethyl acetate)

178 mg of 17- (3-hydroxyprop1 (Z) -enyl) -17β-hydroxy-11β, 19- (4- (1-methyl-1-hydroxyethyl) -o-phenylene] -4-androstene-3 is isolated as a white foam.

[a] D = 61 (CHC1 _3, C = 0.5)

M.p. 208-211 ° C (ethyl acetate)

Example 37

17- (4-Hydroxybutyl] (Z) -enyl) -17 (3-hydroxy]] (3,19 (4-isopropenyl-o-phenylene) -4-androstene-3-ort

a) 17- (4-Hydroxy-but-1-ynyl) -1-1 (3,19- (4-isopropenyl-phenylene) -3,3- (2,2-dimethyl-trimethylenedioxy) -androstane-5o 17 (3-diol g 34b) is dissolved in 60 ml of absolute tetrahydrofuran and 2.27 ml of n-but-1-yn-4-ol and 4.09 g of potassium ethylate are successively added under a protective gas. After the addition and stirring for 14 hours, the reaction mixture is kept at 0 [deg.] C. After pouring into water, the aqueous phase is extracted with ethyl acetate, the combined organic phases are washed with saturated sodium chloride solution, dried over sodium sulfate and concentrated in vacuo. . The residue was chromatographed on aluminum oxide (neutral, activity grade ΠΙ) to afford 1.2 g of the title compound as a white foam: IR (KBr). 2240 ^cm-1 (triple bond)

b) 17- (4-Hydroxybut-1 (Z) -enyl)]] - (3,19- (4-isopmpenyl-o-phenylene) -3,3- (2,2-dimethyl-trimethylene-dioxy) ) -andm-stan-5a, 17 (3-diol ga) was hydrogenated using Lindlar catalyst as in Example 5b). Chromatography on alumina (neutral, activity III) afforded 836 mg of the title compound as a white foam.

c) 17 - (4-Hydroxybut-1 (Z) -enyl) ·! Τβ-hydroxyl (3,19- (4-isopropenyl-o-phenylene) -4-androsten-3-one

800 mg of the material obtained in step b) are cleaved to give 4-ene-3-keto compound as in Example le) After chromatography on silica gel, 306 mg of the title compound is isolated in the form of a white foam.

[a] D = 78 _(CHCl3, c = 0.515)

Example 38

17- (Prop-1-ynyl-17 (3-hydroxy-11 (3,19- [4- (diethoxyphosphoryl) o-phenylene] androsten-3-one)

a) 11,11- (3,19- [4- (Diethoxyphosphoryl) o-phenylene] -5a-hydroxy-3,3- (2,2-dimethyltrimethylenedioxy) -androstan-17-one

1.5 g of the triflate obtained in Example 26b) are dissolved in 10 ml of absolute triethylamine and 122 mg of tetrakis (triphenylphosphine) palladium and 0.46 ml of phosphorous acid diethyl ester are added under a protective gas. The reaction mixture was then refluxed for 1.5 hours. After addition of 100 mg of tetrakis (triphenylphosphine) palladium and 0.46 ml of phosphorous acid diethyl ester, the mixture is refluxed for another 1.5 hours, then allowed to cool to room temperature and concentrated in vacuo. The residue was chromatographed on silica gel to give 1.05 g of the title compound as a white foam.

b) 17- (Prop-1-ynyl) -11- (3,19- [4- (diethoxyphosphoryl) -phenylene] -3,3- (2,2-dimethyl-trimethylenedioxy) -androstane5a, 17 ( The compound prepared in 3-diol (ga) is reacted with propin as in Example 2b. After chromatography on alumina (neutral, ΠΙ activity level), 832 mg of the title compound is isolated in the form of a white foam.

IR (KBr): 2240 cm ^-1 (triple bond)

c) 17- (Prop-1-ynyl) -17H-hydroxy-11 (3,19- [4- (diethoxyphosphoryl) -ophenylene] -androsten-3-one

800 mg of the material prepared in step b) are cleaved to give 4-ene-3-keto compound as in example le). Chromatography on silica gel afforded 440 mg of the title compound as a white foam. [a] g = 17 ”(CHCl ₃ ; c = 0.5)

Example 39

17- (Prop-1-ynyl) -17 (3-hydroxy-11β, 19- [4- (2-thienyl) o-phenylene) -4-androsten-3-one

a) 11 (3,19- [4- (2-Thienyl) -o-phenylene] -3,3- (2,2-dimethyl-trimethylene-dioxy) -distane-5-c, 17 (3-diol)

1.26 g of the product prepared in Example 21a) are dissolved in 36 ml of absolute dioxane and, under a protective gas, 3.04 ml of hexa (n-butyl) dione, 254 mg of lithium chloride and 100 mg of tetrakis (triphenylphosphine) palladium are added. We are added. The mixture was then heated to 110 ° C and maintained at this temperature for 1 hour, followed by addition of 1.94 ml of 2-bromothiophene and stirring at 110 ° C for an additional 18 hours. The reaction mixture was then cooled to room temperature and filtered through celite. After evaporation of the filtrate, the residue is chromatographed on silica gel. This gave 545 mg of the title compound as a yellow foam.

In this type of coupling, the following tin compound is isolated:

HU 210 532 Λ9

α) 11 β, 19- {4- [Tri- (n-butyl) -stanyl] -o-phenylene / 3,3- (2,2-dimethyl-trimethylenedioxy) -androstane-5 (t, 17β-diol)

1.26 g of the compound prepared in Example 21a are reacted with 3.04 ml of hexa (n-butyl) dione under the conditions described in step a). The mixture was heated at 110 ° C for 1 hour and worked up in the usual manner. Chromatography on silica gel afforded 625 mg of the title compound as a white foam.

[α] D = 25 ° (CHCl ₃ ; c = 0.5)

137-139 ° C (diisopropyl ether)

b) 11,19- [4- (2-Thienyl) -o-phenylene] -5a-hydroxy-3,3 (2,2-dimethyl-trimethylenedioxy) -androstan-17-one

400 mg of N-chlorosuccinimide are dissolved in 5 ml of absolute dichloromethane at 0 ° C. After adding 0.3 ml of dimethyl sulfide, the mixture was stirred for 30 minutes at 0 ° C. A solution of 510 mg of the product obtained in step a) in 5 ml of absolute dichloromethane is then slowly added dropwise. The mixture was stirred for 2 hours, except for moisture, and triethylamine (0.6 mL) was added dropwise. The reaction mixture is poured into water, the aqueous phase is extracted with dichloromethane and the organic phase is washed with saturated sodium chloride solution. After drying over sodium sulfate, the solution is concentrated in vacuo. The residue was chromatographed on alumina (neutral, activity III) to isolate 387 mg of the title compound as a yellowish foam.

IR (KBr): 1740 cm ^-1 (5 membered ring ketone)

c) 17- (Prop-1-ynyl) -11β, 19- [4- (2-thienyl) -o-phenylene] 3.3- (2,2-dimethyl-trimethylenedioxy) -androstane-5-c, 17β-diol

350 mg of the product obtained in step b) are reacted with propin as in example 2b). Chromatography on alumina (neutral, activity III) afforded 343 mg of the title compound as a yellowish foam.

IR (KBr): 2240 cm ^-1 (triple bond)

d) 17- (Prop-1-inyl) -17β-hydroxy-7β, 19- [4- (2-thienyl) -o-phenylene] -4-androsten-3-one

320 mg of the compound obtained in step d) are cleaved to give 4-ene-3-keto compound as in example le). After chromatography on silica gel, 234 mg of the title compound is isolated as a yellowish foam.

[a] D = 65 ° (CHC1 _3, C = 0.5)

Example 40

17- (Prop-1-ynyl) -17β-hydroxy-11,19- [4- (3-thienyl) o-phenylene] -4-androsten-3-one

a) 11,19- [4- (3-Thienyl) -o-phenylene] -5a-hydroxy-3,3 (2,2-dimethyl-trimethylene-dioxy) -androstan-17-one

1.26 g of Example 26b are reacted with 2 ml of 3-bromothiophene under conditions similar to those of Example 39a). After chromatography on alumina (neutral, ΠΙ activity level), 546 mg of the title compound is isolated as a yellowish foam.

b) 17- (Prop-1-ynyl) -11β, 19- [4- (3-thienyl) -o-phenylene] -3,3- (2,2-dimethyl-trimethylenedioxy) -androstane-5α, 17β- diol

520 mg of the material prepared in step a) are reacted with propin as in example 2b). Chromatography on alumina (neutral, activity III) afforded 462 mg of the title compound as a yellow foam.

IR (KBr): 2250 cm-1 (triple bond)

c) 17- (Prop-1-ynyl) -7-hydroxy-11,19- [4- (3-thienyl) -o-phenylene] -4-androsten-3-one

410 mg of the material obtained in step b) are cleaved to give 4-ene-3-keto compound as in example le). After chromatography on silica gel, the title compound (287 mg) was isolated as a yellowish foam. [α] D = 61 '(CHCl ₃ ; c = 0.51)

Example 41

17- (Prop-1-inyl) -17 S -hydroxy-11β, 19- [4- (3-furyl) -phenylene J-4-androsten-3-one

a) 1] $, 19- [4- (3-Furyl) -o-phenylene] -5-hydroxy-3,3 (2,2-dimethyl-trimethylenedioxy) -androstan-17-one

1.26 g of the product prepared in Example 26b) are reacted with 1.8 ml of 3-bromofuran as in 39a). Chromatography on silica gel afforded 660 mg of the title compound as a white foam.

240-243 ° C (ethyl acetate)

b) 17- (Prop-1-ynyl) -11,19- [4- (3-furU) -o-phenylene] 3.3- (2,2-dimethyl-trimethylenedioxy) -androstane-5a, 17 $ diol

630 mg of the product obtained in step a) are reacted with propin as in example 2b). After chromatography on alumina (neutral, ΠΙ activity level), 615 mg of the title compound is isolated as a white foam.

IR (KBr): 2240 cm @ -1) 17- (Prop-1-ynyl) -17 S -hydroxy-11,19- [4- (3-furyl) -o-phenylene] -4-androsten-3-one.

590 mg of the product obtained in step b) are converted to the 4-ene-3-keto compound as in Example le) After chromatography on silica gel, 289 mg of the title compound is isolated in the form of a white foam. [α] D = 49 ° (CHCl ₃ ; c = 0.51)

Example 42

17- (Prop-1-ynyl) -17β-hydroxy-11β, 19- [4- (3-methoxyphenyl) -o-phenylene-4-androsten-3-one

a) 11β, 19- [4- (3-Methoxyphenyl) -o-phenylene] -5a-hydroxy-3,3- (2,2-dimethyl-trimethylenedioxy) -androstan-17-one

1.26 g of the product prepared in Example 26b) are reacted with 3-bromoanisole in a similar manner to Example 39a).

Chromatography on silica gel afforded 685 mg of the title compound.

b) 17- (Prop-1-ynyl) -11,19- [4- (3-methoxyphenyl) -o-phenylene] -3,3- (2,2-dimethyl-trimethylenedioxy) -androstane5α7 $ diol

650 mg of the material prepared in step a) are reacted with propin in the same manner as in Example 2b). Chromatography on alumina (neutral, activity III) afforded 635 mg of the title compound as a white foam.

IR (KBr): 2230 cm ^-1 (triple bond)

HU 210 532 A9

c) 17- (Prop-1-ynyl) -17 H -hydroxy-77β, 7 9- [4- (3-methoxyphenyl) phenyl] -4-androsten-3-one

600 mg of the material prepared in step b) are converted to the 4-ene-3-keto compound under conditions similar to those described in Example le). Chromatography on silica gel afforded 366 mg of the title compound as a white foam.

[α] D = 66 ° (CHCl ₃ , c = 0.5)

158-162 ° C (ethyl acetate / hexane)

Example 43

17- (Prop-1-ynyl) -1,7-hydroxy-11β, 19- (4- (4-methoxyphenyl) -o-phenylene] -4-androsten-3-one

a) 11β, 19- [4- (4-Methoxyphenyl) -o-phenylene] -5α-hydroxy-3,3- (2,2-dimethyl-trimethylenedioxy) -androstan-17-one

1.26 g of the compound prepared in Example 26b) are reacted with 2.53 ml of 4-bromo-anisole, as in Example 39a). Chromatography on silica gel gave 522 mg of the title compound as a white foam.

[α] D = 48 ° (CHCl ₃ , c = 0.5)

171-173 ° C (ethyl acetate)

b) 17- (Prop-1-ynyl) -11β, 19- [4- (4-methoxyphenyl) -o-phenylene] -3,3- (2,2-dimethyl-trimethylenedioxy) -androstane diol

500 mg of the material prepared in step a) are reacted with propin in the same manner as in Example 2b). After chromatography on alumina (neutral, activity level III), 498 mg of the title compound is isolated as a white foam.

IR (KBr): 2240 cm ^-1 (triple bond)

c) 17- (Prop-1-ynyl) -17 H -hydroxy-11 H, 19- [4- (4-methoxyphenyl) -o-phenylene] -4-dodsthen-3-one

450 mg of the material prepared in step b) are converted to the 4-ene-3-keto compound as in example le). After chromatography on silica gel, the title compound was isolated as a white foam (276 mg).

[a] D = 70 ° _(CHCl3; c = 0.505)

165-169 ° C (ethyl acetate / hexane)

Example 44

17- (Prop-1-ynyl) -] - 7-hydroxy-77β, 7 9- [4- (2-methoxyphenyl) -o-phenylene] -4-androsten-3-one

a) 11β, 19- [4- (2-Methoxyphenyl) -o-phenylene] -5α-hydroxy-3,3- (2,2-dimethyl-trimethylenedioxy) -andmstan-17-one

1.26 g of the product prepared in Example 26b) are reacted with 2.53 ml of 2-bromo-anisole, as in Example 39a).

Chromatography on silica gel afforded 448 mg of the title compound as a white foam.

b) 17- (Prop-1-ynyl)] - ?, 19- [4- (2-methoxyphenyl) o-phenylene] -3,3- (2,2-dimethyltrimethylene dioxide) -? androsztán5a, 17.beta.-diol

Similarly to Example 2b, 410 mg of the material prepared in step a) is reacted with propine. After chromatography on alumina (neutral, activity level III), 405 mg of the title compound is isolated as a white foam.

IR (KBr): 2240 cm ^-1 (triple bond)

c) 17- (Prop-1-imyl) -17 H -hydroxy-11 H, 19- [4- (2-methoxyphenyl) phenyl] -4-androsten-3-one

380 mg of the material prepared in step b) are converted to the 4-ene-3-keto compound as in example le). Chromatography on silica gel gave 205 mg of the title compound as a white foam.

[α] D = 49 ° (CHCl ₃ ; c = 0.51)

Example 45

17- (Prop-1-ynyl) -17 H -hydroxy-11 H, 19- [45- (methylenedioxy) -phenylene] -4-dodsthen-3-one

a) 19- [2-Chloro-4,5-methylenedioxy-phenyl] -3,3- (2,2-dimethyl-trimethylene-dioxy) -9 (11) -androstene-5a, 17'-diol

As in Example 1a), 10 g of 5a, 10a-epoxy-3,3 (2,2-dimethyltrimethylenedioxy) -9 (11) -estrene-17β-ol was reacted with 6-chloropiperonyl chloride to give 10.3 g of 19- [2-Chloro-4,5-methylenedioxyphenyl) -3,3- (2,2-dimethyltrimethylenedioxy) -9 (11) -androstene-5a, 17β--οόϊ is obtained.

b) 11 µl, 19- [4,5- (Methylenedioxy) o-phenylene] -3,3- (2,2-dimethyltrimethylenedioxy) androstane-5α, 17β-diol

Similarly to Example 1b, 5.9 g of N, 19- [4,5- (methylenedioxy) o-phenylene] 3,3- (2,2-dimethyltrimethylenedioxy) is obtained from the compound obtained in 10 g). androstane5α, 17β-όίοΗ is prepared in the form of a white foam.

c) 11β, 19-4,5-Methylenedioxy) -o-phenylene-5α-hydroxy-3,3- (2,2-dimethyl-trimethylenedioxy) -androstan-17-one

As in Example 2a, the compound obtained in step 5.5 gb) is converted to the corresponding 17α-keto compound. After chromatography, 4.2 g of 11β, 19 ′ [4,5- (methylenedioxy) o-phenylene] -5α-hydroxy-3,3- (2,2-dimethyltrimethylenedioxy) -androstane-17- is isolated in the form of a white foam. [α] D = 45 ° (CHCl ₃ ; c = 0.525)

M.p. 219-222 ° C (ethyl acetate)

d) 17- (Prop-1-ynyl) -yl, 19- (4,5- (methylenedioxy) -phenylene) -3,3- (2,2-dimethyl-trimethylenedioxy) -androstane 5a, 17b- diol

As in Example 2b, 4 g of the compound obtained in step c) are converted to the corresponding 17a-propynyl compound. After chromatography, 3.5 g of 17- (prop-1-ynyl) -1,19- [4,5- (methylenedioxy) o-phenylene] -3,3- (2,2-dimethyltrimethylenedioxy) androstane- 5a, 17-Diol is isolated as a white foam.

IR (KBr): 2230 cm ^-1 (triple bond)

e) 17- (Pmp-1-ynyl) -17 H -hydroxy-11β, 19- (4,5-methylenedioxy-o-phenylene) -4-androsten-3-one

As in Example le), the compound obtained in step 3gd) is converted to the corresponding 4-ene-3-keto compound. 1.36 g of 17- (prop-1-ynyl) -17 [T-hydroxy-1 H, 19- [4,5- (methylenedioxy) o-phenylene] -4-androsten-3-one are isolated. . [α] D = 2 ° (CHCl ₃ ; c = 0.485)

PATENT CLAIMS

Claims (17)

1. 19,11 β-Bridged Steroids of Formula (I): wherein:? R ^{1 is} methyl or ethyl, R ^{2 is} hydrogen, chloro or C 1-4 alkyl, B and G are the same or different, each hydrogen24 A 210, A 9, C 1-4 alkyl, or taken together, represent a second bond between C 6 and C 7, B and R ² together are methylene or ethylene, Z is a group of formula (a) R ¹ is a dotted bond, optionally present, of the formula (I) starting from W W is CH ₂ , CH, CH ₂ CH ₂ or CHCH ₂ , R ⁵ / R ⁶ -O R ⁷ / -C = CU -OR ⁷ / -CO-CH ₂ -R ⁸ -CO-CH ₂ -R ⁸ / -OR ⁷ -CO-CH ₂ -R ⁸ / -CH ₃ -co-ch ₂ -r ⁸ / -h -OR ⁷ / - (CH ₂ ) m -CH ₂ -R ⁹ -OR ⁷ / -CH-CH (CH ₂ ) _k -CH ₂ R ⁹ -0R '° / H -OR ¹⁰ / - (CH ₂ ) _k -C 5 C-U or a group of formula (b) or (c) R ^{7 is} hydrogen or C 1 -C 4 aryl, U is hydrogen, C 1 -C 4 alkyl, hydroxyalkyl, alkoxyalkyl or acyloxyalkyl in the alkyl or acyl moiety or halogen, R ^{8 is} hydrogen, hydroxy, C 1-4 alkyl, C 1-4 O-alkyl, or C 1-4 O-acyl, R ^{9 is} hydrogen, hydroxy or cyano, C 1 -C 4 O-alkyl or C 1 -C 4 O-acyl, R ^{10 is} hydrogen, C 1 -C 10 alkyl or C 1 -C 10 aryl, m is 0, 1, 2 or 3, k is 0, 1 or 2, A phenyl group of formula V (d) or a five or six membered heteroaromatic ring containing 1-2 N, O or S atoms of formula (e) in which R ⁴ and R ⁴ 'are the same or different and are each hydrogen, cyano, -OR ¹¹ -S (O) k R ¹¹ , -IV (O) n R ^12, -OSO ₂ R ¹³ -, -P (O) (OR ¹⁴ ) 2, -SiR ¹⁴ 3, or -Sn R ¹⁴ 3, wherein k is 0, 1 or 2, n is 0 or 1, R ¹ 'is hydrogen or C 1-8 alkyl, R ^{12 has the} same meaning as R ¹¹ , cyano or -C ac acyl, R ^{13 is} perfluorinated C 1 -C 4 alkyl, R ^{14 is C} 1-4 alkyl, or R ¹¹ and R ^{12 are} one within the group -N (O) _n R ⁿ R ¹² - It encloses a nitrogen atom of a 5- or 6-membered heterocyclic group, while N, O or S may be present as another heteroatom in the ring, Y and Y'is identical or different, each of which may be a direct bond, a straight or branched, optionally double or triple bond (s), containing up to 20 carbon atoms, optionally having one or more oxo groups, C 1-10 acyloxy groups , -OR ¹¹ , -S (O) _k R ^H and / or -N (O) _n R ^H R ¹² , optionally substituted arylene, or R ⁴ -Y and R ⁴ '-Y' together form an optionally substituted, saturated, unsaturated or aromatic 5- or 6-membered ring containing 0-2 oxygen atoms, sulfur atoms and / or -NR ¹¹ groups with the proviso that k and n can be greater than 0 only when R ^{11 is C} 1-8 alkyl, and The ring is a) (f) wherein M and N together are a second bond or M is hydrogen and N is hydroxy, with B, R ² , G, R ³ D and E are hydrogen; and X is an oxygen atom, two hydrogen atoms, or a hydroxyimino group of N-OH, R ³ and D are the same or different, each hydrogen, cyano or C 1 -C 4 alkyl or together methylene or ethylene, E is hydrogen, C 1-4 alkyl, D and E together have a second bond between carbon atoms 1 and 2 or a methylene group or (b) a group of formula (g), or c) a group of the formula (h) in which R ^{11 is} hydrogen or (C 1 -C 8) alkyl, and optionally pharmaceutically acceptable acid addition salts thereof. Compounds according to claim 1, characterized in that R ² , B and G are both hydrogen. Compounds according to claim 1, characterized in that B and G together represent a second bond and R ^{2 represents a} hydrogen atom. Compounds according to claim 1, characterized in that Y and Y 'are each a direct bond and that R ⁴ and R ⁴ ' are each hydrogen. Compounds according to claim 1, characterized in that both Y and Y 'are a direct bond, R ^{4 is} hydrogen and R ⁴ ' is nitrogen atom substituted with two C 1 -C 8 alkyl groups. Compounds according to claim 1, characterized in that Y and Y 'are both a direct bond, R ^{4 is a} hydrogen atom and R ⁴ ' is a C 1-8 alkoxy group. Compounds according to claim 1, characterized in that Y is a direct bond, R ⁴ and R ⁴ 'are both hydrogen and Y' is a straight or branched chain alkylene group containing up to 20 carbon atoms, optionally containing double and / or triple bonds. which is substituted with oxo or -OR ¹¹ wherein R 11 is hydrogen or C 1-8 alkyl. Compounds according to claim 1, characterized in that R ⁴ -Y and R ⁴ '-Y' - together form a saturated, unsaturated or aromatic 5- or 6-membered ring having 0-2 oxygen atoms, sulfur atoms and / or NR ¹¹ is wherein R ^{11 is} hydrogen or C 1-8 alkyl. 9. A compound according to claim 1, characterized in that Y'-R ⁴ 'moiety is a hydrogen atom and a group of formula YR ⁴ ethyl, vinyl, isopropyl, isopropenyl, prop-l (Z) -enyl -, prop-1 (E) 25 A 210 enyl, prop-2-enyl, ethynyl, propynyl, prop-2-ynyl, methoxy, thiomethyl, thioethyl, 1-hydroxyethyl or diethoxyphosphoryl, substituted or unsubstituted carbocyclic or heterocyclic aryl. Compounds according to claim 9, characterized in that the aryl group is phenyl, naphthyl, 2-methoxyphenyl, 3-methoxyphenyl, 4-methoxyphenyl, 2-tolyl, 3-tolyl -, 4-tolyl, 2-dimethylamino, 3-dimethylamino, 4-dimethylamino, furyl-2, furyl-3, thienyl-2, thienyl-3, pyridyl-2- , pyridyl-3, pyridyl-4, thiazolyl, imidazolyl. Compounds according to claim 1, characterized in that the 5- or 6-membered heteroaromatic ring is furyl, thienyl, pyridyl, pyrazolyl, pyrrolyl, pyrimidinyl, oxazolyl, pyridazinyl, pyrazinyl. 12. A compound of formula (II) wherein R * is methyl or ethyl 1 is 1 or 2, K is a ketone protected in ketal or thioketal form, and V 'is a phenyl group of formula (i) or a 5- or 6-membered heteroaromatic ring of formula (j) containing 1-2 N, O or S atoms fluorine, chlorine, bromine or iodine, R ^4a , R ^4a ', Y ^a , Y' ^{a, with} the exception ^of the cyano group, have the same meaning as given for R ⁴ , R ⁴ ', Y and Y' in the formula (I), with the hydroxy, mercapto, amino , oxo and / or terminal acetylene groups are protected. 13. 19,11 β-Bridged Steroids of Formula IV, wherein R ^{1 is} methyl or ethyl 1 is 1 or 2, K is a ketone protected in the form of a ketal or thioketal, and a phenyl group of the formula V or a 5- or 6-membered heteroaromatic ring of the formula N containing 1 to 2 N, O or S atoms in the formulas R ⁴³ , R ^4a ', Y ^a , Y' ^a other than cyano R ⁴ , R 4 ', Y and Y' have the same meaning as given for formula (I), with the hydroxy, mercapto, amino, oxo and / or terminal acetylene groups optionally present, Q being R ⁵ and S being R ⁶ are identical or together form a ketooxygen atom. 14. A process for the preparation of a compound of formula I wherein: R * is methyl or ethyl R ^{2 is} hydrogen, chloro or C 1-4 alkyl, B and G, the same or different, are each hydrogen, C 1 -C 4 alkyl, or taken together to form a second bond between C 6 and C 7, B and R ² together are a methylene or ethylene group Z is a group of formula (a) wherein R ¹ is a dashed line of formula (I) starting from W W is CH ₂ , CH, CH ₂ CH ₂ or CHCH ₂ , R ⁵ / R ⁶ -OR ⁷ / -C = CU, -OR ⁷ / -CO-CH ₂ -R ⁸ -CO-CH ₂ -R ⁸ / -OR ⁷ -co-ch ₂ -r ⁸ / -ch ₃ -co-ch ₂ -r ⁸ / -h -OR ⁷ / - (CH ₂ ) _m -CH ₂ -R ⁹ -OR ⁷ / -CH = CH ₂ (CH ₂ ) _k -CH ₂ -R ⁹ -OR '° / H -OR '° / - (CH ₂ ) k C = CU or a group of formula (b) or (c) wherein R ^{7 is} hydrogen or C 1 -C 4 acyl, U is hydrogen, C 1 -C 4 alkyl, hydroxyalkyl, alkoxyalkyl or acyloxyalkyl in the alkyl or acyl moiety or halogen, R ^{8 is} hydrogen, hydroxy, C 1-4 alkyl, C 1-4 O-alkyl, or C 1-4 O-acyl, R ^{9 is} hydrogen, hydroxy or cyano, C 1 -C 4 O-alkyl or C 1 -C 4 Oacyl, R ^{10 is} hydrogen, C 1 -C 10 alkyl or C 1 -C 10 acyl, m is 0, 1, 2 or 3, k is 0, 1 or 2, V is a phenyl group of formula (d) or a five- or six-membered heterocyclic group containing 1-2 N, O or S atoms of formula (e) in which R ⁴ and R ⁴ 'are the same or different and are both hydrogen or cyano, -OR ", -S (O) k R", N (O) n R "R ¹² -, -OSO ² R ¹³ -, -P (O) (OR ^I4) 2, -SiR ⁴ 3 or -SnR ¹⁴ 3 group in these k is 0, 1 or 2, n is 0 or 1; R "is hydrogen or (C 1 -C 8) -alkyl, R ^{12 has the} same meaning as R", cyano or (C 1 -C 10) acyl, R ^{13 is} perfluorinated C 1 -C 4 alkyl, ^R14 is C1-4 alkyl, or R "and R ¹² -N (O) _n R" ¹² - within a group are enclosed in a 5- or 6-membered heterocyclic nitrogen, whereby the ring one additional heteroatom selected from N, O or S may be present, Y and Y 'are identical or different, each of which may be a direct bond, a straight or branched, optionally double or triple bond (s), containing up to 20 carbon atoms, optionally having one or more oxo groups, C 1-10 acyloxy groups, -OR ", -S (O) _k R" and / or -N (O) _n R "R ₁₂ , optionally substituted arylene, or R ⁴ -Y and R ⁴ '-Y' together form an optionally substituted, saturated, unsaturated or aromatic 5- or 6-membered ring containing from 0 to 2 oxygen atoms, sulfur atoms and / or -NR ', with the proviso that k and n are greater than 0 only when R 'is a C 1-8 alkyl group and is The ring is a) (f) wherein M and N together are a second bond or M is hydrogen and N is hydroxy, B, R ² , G, R ³ , D and E being hydrogen; HU 210 532 A9 X is an oxygen atom, two hydrogen atoms, or a hydroxyimino group of N-OH, R ³ and D are the same or different, each hydrogen, cyano or C 1 -C 4 alkyl or together methylene or ethylene, E is hydrogen, (C 1 -C 4) -alkyl D and E together with C 1 and C 2 is a second bond or a methylene group, or (b) (g) or (c) (h), wherein R ^{11 is} hydrogen or C 1 -C 8 alkyl, and optionally pharmaceutically acceptable acid addition salts thereof, characterized in that a compound of formula II wherein R ^{1 is} methyl or ethyl 1 is 1 or 2, K is a ketone protected in ketal or thioketal form, and a phenyl group of formula V '(i) or a 5- or 6-membered heteroaromatic ring of formula (j) Containing 1 to 2 N, O or S atoms in the formulas: Halfluorine, chlorine, bromine or iodine, R ^4a , R ^4a , Y ^a , Y ' ^{a, with} the exception ^of the cyano group, have the same meaning as given for R ⁴ , R ⁴ ', Y and Y 'in the general formula (I), with the optionally present hydroxy, mercapto, amino, oxo - and / or terminal acetylene groups are protected by treatment with one or more organic solvents in liquid ammonia with an electropositive metal or, when the N-halogen substituent bromine or iodine in the compound of formula (Π) is reduced by the reductive radical method (Va) cyclizing to an intermediate in this formula A phenyl group of formula V (m) or a 5- or 6-membered heteroaromatic ring of formula (n) containing 1 to 2 N, O or S atoms in the formulas R ⁴³ , R ^4a ', y ^a , y' ^{a have} the same meaning as R ⁴ , R ⁴ , 'Y and Y * except ^for the cyano group, with the hydroxy, mercapto, amino, oxo and / or the terminal acetylene groups are protected, Q is only a β-hydroxy group and S is an α-hydrogen atom, and subsequently a) oxidizing the C-17 hydroxy group and then b) removing the protecting group from the hydroxy optionally having a protecting group in V ', optionally preparing the appropriate C 1 -C 4 perfluoroalkyl sulfonate, optionally the perfluoroalkyl sulfonate or the perfluoroalkyl sulfonate, in the hydroxy compound; converting the leaving group to a tin-trialkyl group via the appropriate tin-trialkyl compound obtained in the V, optionally having further desired substituents after further reactions, or first step b) and then step a), and then c) preparing the substituents on the D ring in a manner known per se, treating the product thus obtained with a dehydrating agent which is also capable of liberating the 3-oxo group and simultaneously cleaving the 4 (5) double bond with water; and / or Z in the substituents Z are protected again by introducing the desired groups into the A and B rings of the steroid backbone, or d) treating the resultant product with a dehydrating agent, which is also suitable for liberating the 3-oxo group, simultaneously forming a 4 (5) double bond in the water cleavage, introducing the desired substituents into the A and B rings of the steroid skeleton; After protecting the 3-oxo group, the D ring is provided with the desired groups or the steps a) and b) are carried out after steps c) and d), the resulting product is optionally deprotected, optionally with the hydroxy present in V alkylating and / or acylating the mercapto and / or amino groups, optionally introducing a cyano group into the aryl group (s), optionally oxidizing the amino and / or sulfate groups optionally present in the aryl substituents, optionally with hydroxylamine hydrochloride to form a compound of formula I wherein X is an N-OH hydroxyimino group and optionally a pharmaceutically acceptable salt thereof a tolerable acid addition salt is prepared. 15. The process of claim 14, wherein the electropositive metal is cyclized with sodium, lithium, potassium or calcium. 16. A pharmaceutical composition, characterized in that it is a compound of claims 1-11. A compound according to any one of claims 1 to 4. 17. Use of compounds according to claims 1 to 8 for the preparation of a medicament.